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First published online 14 May 2008
doi: 10.1242/dev.014498
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Review |
Biozentrum der Universität Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland.
* Author for correspondence (e-mail: Markus.Affolter{at}unibas.ch)
SUMMARY
Our understanding of the molecular control of morphological processes has increased tremendously over recent years through the development and use of high resolution in vivo imaging approaches, which have enabled cell behaviour to be linked to molecular functions. Here we review how such approaches have furthered our understanding of tracheal branching morphogenesis in Drosophila, during which the control of cell invagination, migration, competition and rearrangement is accompanied by the sequential secretion and resorption of proteins into the apical luminal space, a vital step in the elaboration of the trachea's complex tubular network. We also discuss the similarities and differences between flies and vertebrates in branched organ formation that are becoming apparent from these studies.
Introduction
Branching morphogenesis restructures epithelial sheets to give rise to
organs of fascinating three-dimensional architecture, as exemplified by the
adult lung, the kidney and the vasculature in humans. In Drosophila
melanogaster, genetic studies have provided much insight into the
regulatory networks that regulate the ordered formation of tracheal branches
in the embryo, and into how the different branches coordinate their relative
sizes, an issue that is of importance to the physical aspects of branched
organ function (Affolter et al.,
2003
; Ghabrial et al.,
2003; Uv et al.,
2003). More recently, the development of live-imaging approaches
in Drosophila have allowed researchers to take a deeper look at the
behaviour of cells during the branching process, and have enabled events at
the molecular level to be linked to the behaviour of individual cells or
groups of cells.
This combination of molecular genetics and live-imaging techniques has provided investigators with a unique opportunity to understand the morphological processes that occur during branching morphogenesis. This review focuses and builds on some of these recent insights, and assesses how they have led to a better understanding of the cellular and molecular processes that contribute to the transformation of simple, two-dimensional epithelial sheets into fascinating, three-dimensional tubular structures that can perform important functions in development and homeostasis. We focus here on the Drosophila tracheal system because several cellular and molecular paradigms, such as cell migration, competition and rearrangement, as well as the elaboration of a complex apical luminal environment, have recently been uncovered in this system that might serve related roles in the formation of other branched organs or tissues; these similarities might help us in the future to gain an even better understanding of how morphogenesis in general is regulated during development.
Tracheal development in the fly embryo
The complex structure of the tracheal system consists of interconnected,
metameric units of different-sized tubes that extend over the entire embryo
shortly before hatching (Samakovlis et
al., 1996b) (see Fig.
1, see also Movie 1 in the supplementary material). The metameric
units begin their development independently during germ band extension, as
groups of tracheal cells are set aside from the neighbouring epidermal cells
and invaginate to form a sac-like tracheal structure. This structure generates
the luminal cavity, which is subsequently expanded and remodelled during the
branching process. Those tracheal cells in this sac-like invagination that are
close to Branchless (Bnl)/Fibroblast growth factor (Fgf)-secreting
(non-tracheal) cells adopt migratory properties and move toward the sources of
Bnl/Fgf, while remaining attached to their tracheal neighbours. This results
in the formation of interconnected, bud-like extensions.
Through extensive cell rearrangements and cell shape changes, these buds elongate to form branches of distinct cellular architecture, ranging from multicellular tubes to fine branches, in which cells are arranged in a head-to-tail-like fashion. Upon the interconnection of the metameric, branched units at distinct fusion points, specialized terminal tracheal cells at the periphery of the tracheal system extend the luminal space into individual cell extensions, which adopt tree-like structures and reach virtually every cell with a branch tip. It is at the tip of these fine, intracellular tubes that gas is exchanged with the surrounding tissue.
Research in the past few years has uncovered a series of interconnected cellular choreographies that are regulated by cell-cell signalling, by intracellular events controlling cell shape and motility, and by the sequential control of cell behaviour through apically secreted, luminal proteins. Similar scenarios might underlie branching morphogenesis in other organs systems, and we will mention a few such similarities that have recently emerged.
Forming a sac from a planar epithelium
The formation of epithelial invaginations is of crucial importance and sets
the stage for the ultimate development of the individual metameres of the
tracheal system. Although considered to be a simple step, epithelial
invagination is a process in which genes control the local formation and
proper exertion of tissue forces, and its genetic dissection is a rather
difficult task, as forces are already acting at earlier embryonic stages.
Groups of epidermal cells are determined to become tracheal cells, in part, by
their expression of a combination of transcription factors, including
trachealess (trh), ventral veins lacking
(vvl; also known as ventral veinless) and
knirps/knirps-related (kni/knrl; also known as
knirps-like) (reviewed by Affolter
and Shilo, 2000). In an ordered choreography, these cells then
invaginate while remaining attached to each other and to the neighbouring,
non-tracheal cells.
As none of the cellular activities seen during invagination occur in
trh mutants (Wilk et al.,
1996), the identification and analysis of trh target
genes and their effects on cell behaviour, protein localization, etc., should
provide insight into how the flat epithelial sheet starts its transformation
towards a branched organ. In a recent study, the careful analysis of cell
behaviour in wild-type Drosophila embryos and in embryos mutant for
Trh target genes did indeed lead to a two-step model in which trh
induces and then organizes tracheal invagination
(Brodu and Casanova, 2006)
(see Fig. 2). In the first
step, trh expression outlines an invagination field, a region of
cells that acquire the competence to ingress or sink into the embryo.
Relatively little is known about how this competence to `invaginate' is
molecularly brought about. However, Trh activity initiates a second step, the
activation of Epidermal growth factor receptor (Egfr) signalling through the
transcriptional activation of rhomboid (rho). rho
encodes a transmembrane protein that specifically cleaves the Egf ligand and
thus triggers the activation of the Egf pathway in tracheal cells. Egfr
pathway activity appears to be tightly controlled within the placode. It is
partly suppressed dorsally by the expression of sal (also known as
spalt), which encodes a zinc finger transcription factor, leading to
the observed asymmetry in invagination along the dorsoventral axis. In
addition, the careful examination of cell behaviour and myosin localization
during the invagination process has revealed that the Egf pathway is activated
in a wave, which extends from the centre of the placode, where cells initially
constrict apically, to the outer cells, coordinating the timing and
positioning of intrinsic cell internalization activities
(Nishimura et al., 2007). Egfr
signalling eventually translates into an ordered apical distribution of actin
and myosin, which presumably generates the forces that lead to invagination
via actomyosin contraction. Another Trh target, crossveinless c
(cv-c), which encodes a Rho-GAP enzyme, provides a key step in proper
apical actomyosin distribution, presumably by regulating the activity of the
small GTPase Rho1 (Brodu and Casanova,
2006). Loss of Cv-c results in a variably penetrant tracheal
phenotype that resembles the phenotype caused by an absence of Egfr
signalling. Because Egfr signalling is also required, in cooperation with Trh,
for cv-c expression, it is likely that Egfr activity in tracheal
invagination is, at least in part, mediated by the function of Cv-c in the
apical localization of actomyosin.
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Forming branches
The role of cell migration
It has been known for several years that directed cell migration is the
major cellular activity that underlies the branching process of the developing
tracheal system. Tracheal cells express a Fgf receptor, encoded by the
breathless (btl) locus
(Klambt et al., 1992), as well
as a Fgf-specific signalling adaptor protein encoded by
downstream-of-Fgfr (dof; also known as stumps)
(Vincent et al., 1998;
Imam et al., 1999;
Petit et al., 2004;
Wilson et al., 2004). As for
rho and cv-c expression (discussed above), btl and
dof expression also require the Trh transcription factor, and the
accumulation of btl and dof clearly distinguishes tracheal
cells from neighbouring, non-tracheal, cells and prepares them for the
branching process.
Upon invagination, tracheal cells migrate towards neighbouring cells or
towards tissues that express the Btl ligand Bnl/Fgf; it is the spatial control
of Bnl/Fgf secretion in the Drosophila embryo that ultimately
controls the migratory behaviour and the direction of tracheal cell movement
(Sutherland et al., 1996).
Cells at the tip of tracheal branches (so-called tip cells) appear to be
highly dynamic when visualized in live embryos with confocal microscopy; they
send out filopodia and lamellipodia in response to Btl/Fgfr signalling. Stalk
cells, which link the tip cells to the other tracheal branches, do not form
such extensions (Ribeiro et al.,
2002) (Fig. 3). In
the complete absence of Fgfr signalling, cells remain in the sac-like
configuration, and filopodia or lamellipodia are not seen
(Ribeiro et al., 2002),
demonstrating that Bnl/Fgf signalling regulates both the motility and the
directionality of tracheal cell movement in the embryo.
Another important role of Fgf signalling during the branching process is
the induction of Notch signalling. High levels of Fgf signalling in the tip
cell of primary branches lead to the activation of the Notch (N) ligand Delta
(Dl) (Llimargas, 1999;
Steneberg et al., 1999;
Ikeya and Hayashi, 1999). Dl
expressed in tip cells activates N in neighbouring stalk cells. This N
activation inhibits or reduces Fgf signalling in the neighbouring stalk cells,
in part through the inhibition of activated Extracellular signal-regulated
kinase (Erk) (Ikeya and Hayashi,
1999). Both Fgf and N signalling are involved in cell fate choice
during the branching progress, and ensure that the correct number of fusion
and terminal cells are generated at branch tips (reviewed by
Zelzer and Shilo, 2000). Thus,
Fgf induces not only migratory cell behavior in tip cells, but also, via N
activation, cell fate choices through lateral inhibition mechanisms.
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;
Cabernard and Affolter, 2005)
(see Fig. 4). Genetic mosaic
analysis has shown that cells with reduced Btl/Fgfr are found much less often
at the tips of branches in the third instar stage than are cells with more
receptor molecules (Ghabrial and Krasnow,
2006). Therefore, cells appear to compete for the leading
position, such that those cells with the highest Bnl/Fgf receptor activity
take the lead position, whereas cells with less activity assume subsidiary
positions and form the stalk. In the same study, Ghabrial and Krasnow propose
that this competition involves N signalling, leading to lateral inhibition
that prevents additional cells from taking up the lead position
(Ghabrial and Krasnow, 2006).
Unfortunately, the N studies in this particular case did not involve a careful
genetic mosaic analysis, but relied on the general expression of a
dominant-active form of N and on the analysis of a N thermo-sensitive
mutation. To link more definitively this competition for the leading tip cell
position to N/Dl signalling requires more detailed genetic mosaic studies.
These and earlier studies have clearly attributed a key role to Fgf
signalling in guiding branch budding and outgrowth in the embryo, and in
particular they have linked Fgf signalling to directed cell migration and
altered cytoskeletal dynamics. Furthermore, elegant studies have shown that
Bnl also mediates the ramification of fine terminal branches in response to
oxygen in Drosophila larvae
(Jarecki et al., 1999). During
larval life, oxygen deprivation stimulates the expression of Bnl, and the
secreted growth factor functions as a chemoattractant that guides new terminal
branches towards the expressing cells. Thus, a single growth factor is
reiteratively used to pattern each level of tracheal branching, and the change
in branch patterning results from a switch from developmental to physiological
control of its expression. How the spatially restricted Fgf ligand Bnl
regulates cytoskeletal dynamics at the molecular level is a key question that
remains rather obscure. Only very few zygotic mutations with altered Fgf
signalling levels in tracheal cells have been identified
(Hacohen et al., 1998;
Dammai et al., 2003). This is
mostly because large maternal stores exist of many of the important components
of this process, which hinder genetic approaches to identifying these
components in embryos. However, many maternally provided transcripts and
proteins have been used up by the third instar larval stages, and this has
allowed researchers to use genetic mosaic analysis to investigate whether a
given gene is specifically required for air sac primordia formation in an
otherwise heterozygous animal, as discussed in more detail below.
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).
Tracheal cells in close vicinity to Bnl-secreting cells in the wing imaginal
disc start to proliferate and migrate towards Bnl-expressing cells. Because
tracheal cells divide during this process, somatic genetic mosaic approaches
can be used to study the requirement of various genes for Fgf signalling
and/or air sac primordium formation
(Cabernard and Affolter,
2005). Such mosaic analysis allows researchers to determine
whether a given gene is specifically required for air sac primordia formation
in an otherwise heterozygous animal, and, by using such an approach, Cabernard
and Affolter showed that Fgf directs cell migration at the tip of the
outgrowing branch (Cabernard and Affolter,
2005). Tracheal cells that lack Btl/Fgfr, or the downstream
signalling component Dof, are never found at the leading front of the
outgrowing air sac. Fgf signalling requires Ras function, the Map kinase
pathway and the transcription factor Pointed. More recently it has been
demonstrated that tracheal cells also require heparan sulphate proteoglycans
(HSPGs) to respond to Bnl/Fgf; interestingly, HSPGs are not required for the
secretion and distribution of Bnl/Fgf in the embryo, nor in the later
developmental stages (Yan and Lin,
2007).
Although these analyses have shed some light on the molecular pathway
involved in Fgf signalling in branching morphogenesis, unbiased screens for
additional components will be essential to follow the Fgf signal as it
propagates in responding cells. A first screen aimed at the identification of
genes involved in Fgf-dependent cell migration that used genetic mosaic
analysis in the developing air sac primordium has recently been published
(Chanut-Delalande et al.,
2007). Approximately 30 mutants have been recovered from this
screen that show altered cell migration behaviour, an indication that the
corresponding wild-type protein might play a role in, or downstream of, Fgf
signalling. In this initial analysis, two genes were identified as being
important for Fgf-dependent cell migration, Myosin heavy chain (Mhc) and
Signal transducing adaptor molecule (Stam). Mhc has also been shown to be
involved in border cell migration
(Borghese et al., 2006), while
the isolation and characterization of Stam suggests that trafficking
of Fgfr-containing vesicles plays an important role in efficient cell
migration. Previous studies have also shown that Drosophila abnormal wing
discs (awd), the homologue of human NM23, regulates Fgf
receptor levels and functions synergistically with shibire (also
known as dynamin) during tracheal development
(Dammai et al., 2003). The
exact biochemical functions of Awd and the vertebrate homologues remain to be
elucidated. Further studies of these genes, as well as the identification and
characterization of the other genes mutated on those chromosomes that
co-segregate with impaired tracheal cell migration efficiency in homozygous
clones, will hopefully contribute to a much better understanding of the
molecular aspects of Fgf signalling in branching morphogenesis.
The role of cell intercalation
As mentioned above, the tracheal network consists of tubes of different
size and architecture, ranging from multicellular tubes to unicellular tubes
and intracellular tubes (Samakovlis et
al., 1996b; Uv et al.,
2003). We can thus reformulate the problem of tracheal
morphogenesis and present it as a problem of epithelial remodelling, in which
a flat epithelial sheet is transformed into different cellular arrangements
that organize cells into tube structures in a stereotypic manner. Because each
epithelial cell in a flat sheet has on average six neighbours, the formation
of tubes, in which single cells are arranged in a chain-like, head-to-tail
arrangement, requires extensive epithelial remodelling and the loss of
junctional contact with four of the six initial neighbours
(Fig. 5). To describe these
cell rearrangements, a detailed characterization of the formation of the
dorsal branch has been undertaken using high-resolution live imaging with a
GFP-fusion protein that labels adherens junctions (AJs)
(Ribeiro et al., 2004). These
studies have shown that highly controlled cell intercalations, which require
extensive AJ remodelling, are key to the formation of fine tracheal branches.
Based on these studies and on single-cell analysis, a four-step model of tube
remodelling has been proposed (Ribeiro et
al., 2004) (see Fig.
5). In an initial step (pairing), tracheal cells appear to pair up
along the bud axis. Subsequently, in the `reaching around the lumen' step,
individual cells reach around the lumen to establish contacts with themselves
and start to form the first autocellular AJs. These autocellular AJs, which
are made up of E-cadherin complexes anchored in the same cell, extend and
zipper up as the two initially paired cells appear to slide past each other
and intercalate (the `zipping up' step). In order not to lose all
intercellular AJs (such a loss would cause the cells to dissociate from each
other), the two cells, which have rearranged from a side-by-side to a
chain-like head-to-tail arrangement, need to stop the transformation of
intercellular AJs into autocellular AJs (the `termination' step). The entire
intercalation process takes 20 to 30 minutes and occurs in most tracheal
branches, except in the largest tube of the tracheal system, the dorsal trunk,
which represents a multicellular tube.
Obviously, several questions come to mind when looking at this incredible epithelial remodelling. Where do the forces that trigger intercalation come from? How is AJ remodelling achieved such that the participating epithelial cells remain tightly attached to each other during intercalation? What is the role of junctional proteins and their upstream and downstream regulators during intercalation? Why does the transformation of intercellular AJs into autocellular AJs stop at some point? And how is intercalation regulated in the different tracheal branches to give rise to tubes of different cellular architecture?
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). Both Pio and Dp proteins contain a zona pellucida (ZP)
domain and are apically secreted into the luminal space of the developing
tracheal system. Dp, in addition to its ZP domain, contains hundreds of Egf
repeats interspersed with 21-residue-long, so-called, Dumpy (DPY) modules,
and, at roughly 21,000 amino acids, it is the largest known
Drosophila protein (Wilkin et
al., 2000). As ZP domains form fibrillar structures (reviewed by
Jovine et al., 2005), these
studies strongly suggest that an apical extracellular matrix (ECM) that
contains Pio and Dp provides a structural meshwork in the luminal space,
around which cell rearrangements can take place in an ordered fashion and
without losing interconnections. A physical barrier in the luminal space might
be the most efficient molecular way to inhibit cells from transforming all of
their intercellular AJs into autocellular AJs during intercalation, which
would inevitably lead to a dissociation of neighbouring, fully intercalated
cells. These studies represented the first identification of a luminal protein
that has a key architectural role in tube formation.
The genetic analysis of cell intercalation during branch formation has also
led to the identification of an important developmental regulator of cell
intercalation. The only branches that never contain cells with autocellular
AJs are those that eventually form the dorsal trunk, which, when
interconnected, forms the largest tube of the tracheal system. The dorsal
trunk is also the only tracheal tube in which all cells express the zinc
finger transcription factor Sal (Kuhnlein
and Schuh, 1996). Loss- and gain-of-function genetic studies,
including single-cell analyses (Ribeiro et
al., 2004), have demonstrated that Sal is indeed responsible for
inhibiting cell intercalation and the formation of autocellular AJs in the
dorsal trunk, and it can potently and completely inhibit intercalation when
ectopically expressed in dorsal branches. How Sal inhibits intercalation
remains unknown.
Additional genetic analyses have identified a few more molecular players
that are involved in junctional remodelling during tracheal development. In
mutants that lack the MAGUK protein Polychaetoid (Pyd; also known as ZO-1),
the Drosophila homologue of the junctional protein ZO-1, cell
intercalation is impaired in the sense that the zipping process, or the
conversion of intercellular AJs into autocellular AJs, is incomplete
(Jung et al., 2006). As Pyd
localizes to the AJs in tracheal cells, this protein might play a direct role
in the regulation of the dynamic state of the AJ during epithelial
remodelling. In a different study, the strength of Egfr signalling in tracheal
cells was proposed to regulate the maintenance of tissue integrity, partly by
regulating the cadherin-based modulation of cell adhesion
(Cela and Llimargas, 2006).
However, the timing of Egfr signalling during branch outgrowth and the exact
consequence of the signalling remain to be investigated in detail. In
addition, Src and Rac have also been shown to play important roles in the
maintenance of AJs during tracheal epithelial morphogenesis, through the
regulation of E-cadherin levels (Chihara
et al., 2003; Shindo et al.,
2008). Src appears to play a dual role during tracheal
morphogenesis: it increases the rate of AJ turnover by reducing E-cadherin
protein levels and, simultaneously, stimulates E-cadherin transcription
(Shindo et al., 2008). These
studies suggest that the opposing outcome of Src activation on E-cadherin
facilitates the efficient exchange of AJs that is necessary during the
remodelling and intercalation process. Together, these studies point to an
important role for the proper regulation of adhesive strength in tracheal
cells, and it will be interesting to see how the different pathways interact
with each other. However, whether Sal inhibits cell intercalation via the
regulation of these molecular modules acting at cell-junction complexes
remains an open question.
From branches to functional tubes: regulating the luminal space
In the past few years, much has been learned about how the epithelial cells
that form the three-dimensional network of tubes control tube size, extension
and length, and how the liquid-filled luminal space is emptied and ultimately
filled with gas, allowing the trachea to carry out its assigned function, the
efficient transport of air. In a genetic screen performed by Beitel and
Krasnow, mutations that affect tube shape (e.g. size, length or diameter) were
described (Beitel and Krasnow,
2000). The identification and cloning of the genes affected in
these and other mutants has shed light on how the specialized apical secretion
of ECM material contributes to tube expansion and tube length control.
Although the observed size differences between distinct tracheal branches
is probably controlled by those genes that regulate branch identity (for
example, by the presence or absence of Sal in the cells of the dorsal trunk
and the dorsal branches, respectively)
(Ribeiro et al., 2004;
Neumann and Affolter, 2006;
Casanova, 2007), the diameter
of certain tubes expands rapidly in a relatively short time frame. The uniform
expansion of tube diameter requires the formation of a transient luminal
chitin-based matrix (Araujo et al.,
2005; Moussian et al.,
2006; Tonning et al.,
2005; Devine et al.,
2005) (reviewed by Swanson and
Beitel, 2006) (see Fig.
6). In the absence of the chitin matrix, the lumen dilates in an
uncoordinated fashion, resulting in cystic tubes. The matrix might provide
either a physical scaffold that defines the shape of the tube cells
surrounding it or it could signal to tracheal cells to adjust their shape in a
uniform manner. In addition, the specific chemical modification of the luminal
chitin matrix via apically secreted chitin deacetylases appears to be crucial
for tracheal tubes to obtain the proper length
(Luschnig et al., 2006;
Wang et al., 2006), in line
with the observation that tube length and tube dilation are under separate
genetic control (Beitel and Krasnow,
2000). It is thought that one of these putative chitin
deacetylases, encoded by a gene called vermiform (verm;
LCBP1 - FlyBase), is delivered to the apical lumen via a specialized
secretory pathway that requires septate junctions; this is suggested by the
observation that Verm is not properly secreted into the luminal space in
several mutants of septate junction components, whereas Pio, for example, is
normally secreted into the apical luminal space in the same mutants
(Luschnig et al., 2006;
Wang et al., 2006). The lack
of Verm secretion in many septate junction mutants could indeed account for
the tube-length-expansion defects that are observed in the absence of several
septate junction components (such as Claudin, Megatrachea, Neurexin IV,
Gliotactin and Neuroglian) (reviewed in
Swanson and Beitel, 2006), but
the exact role of septate junction components in secretion remains to be
investigated.
A novel type of tracheal tube expansion gene is polished rice
(pri; also known as tarsal-less), which is transcribed into
a polycistronic mRNA that encodes multiple evolutionarily conserved open
reading frames of 11 or 32 amino acids
(Kondo et al., 2007).
pri functions non-cell autonomously, indicating that these small
peptides might travel through extracellular space to coordinate ECM
organization. In the absence of pri, apical cuticular structures are
completely eliminated, leading to defective tube expansion. Pri is essential
for the formation of the specific F-actin bundles that prefigure the formation
of the taenidial fold pattern of the tracheal cuticle. A novel formin with a
similar role in actin organization has also been reported recently
(Matusek et al., 2006).
Although the accumulation of discrete apical luminal matrices has clearly
emerged as a key feature in the proper regulation of branching morphogenesis
in the developing tracheal system, it is also clear that these matrices have
to be removed or remodelled before the tracheal system can take over its
assigned function. Based on an elegant study combining live imaging and
genetic analysis, it has been proposed that tube maturation comprises three
distinct epithelial transitions (Tsarouhas
et al., 2007). First, a secretion burst deposits luminal proteins
into the luminal space, leading to the rapid expansion described above. In a
second step, the solid luminal material is rapidly cleared from the lumen,
and, shortly afterwards, the liquid is removed. Genetic studies implicate exo-
and endocytosis components in lumen expansion and solid matrix clearance,
respectively (Tsarouhas et al.,
2007; Behr et al.,
2007).
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Thus far, we have only discussed how the initial luminal space is created and remodelled during the invaginations of the tracheal placodes during branching, and how it is cleared of protein and liquid material. However, for the trachea to be functional, new tubes and/or luminal spaces have to be generated de novo in specific cells, either to interconnect individual metameres via specialized fusion cells, or to allow the air to diffuse to the tip of the fine extensions formed by highly specialized terminal cells.
Although de novo lumen formation is an intriguing process, very little is
known about the molecules that form extended luminal cavities inside cells in
vivo during branching morphogenesis. The process is best understood during the
fusion of tracheal tubes. The branches that ultimately form the dorsal trunk
and the lateral trunk meet at specific locations at segment boundaries, and
the dorsal and ventral (ganglionic) branches meet at the dorsal and ventral
midline, respectively (Samakovlis et al.,
1996b). The branch fusion process is initiated by specialized
fusion cells at the tip of each of these branches. When two fusion cells of
adjacent branches contact each other, they first establish a new AJ between
them (Samakovlis et al.,
1996a; Tanaka-Matakatsu et
al., 1996). Inside these fusion cells, tracks of microtubules
associated with F-actin and vesicles align in a pattern that prefigures the
luminal axis (Lee and Kolodziej,
2002). Upon this alignment, the plasma membranes appear to
invaginate along the future luminal axes from the pre-existing luminal sides
toward the newly formed AJs. Finally, the lumen passes through the fusion
cell, suggesting that localized plasma membrane fusion events have occurred.
Recent studies have identified several fusion-cell-specific proteins with
important roles in fusion, such as a formin protein
(Tanaka et al., 2004) and an
Arf-like 3 small GTPase (Jiang et al.,
2007; Kakihara et al.,
2008). In the absence of this Arf-like GTPase, the initial steps
in the fusion process are normal (determination and adhesion of fusion cells,
formation of F-actin bundles and vesicles), but the newly formed luminal
cavities do not open up. Live imaging studies and genetic analysis suggest a
failure in the localized assembly of the exocyst complex, implicating the
targeting of the exocytosis machinery to specific apical domains as being a
key step in lumen fusion.
De novo lumen formation is also essential for the formation of another
specialized cell type in the tracheal system, the terminal cell
(Guillemin et al., 1996).
Terminal cells form the periphery of the tracheal system and extend numerous,
long projections towards target tissues. A lumen then forms within each of
these projections by a poorly understood process that creates an
intracellular, membrane-bound channel without any associated AJs or septate
junctions. Although genetic mosaic analyses have identified a number of
mutations that result in the absence of a lumen in terminal cells
(Baer et al., 2007) (see also
Levi et al., 2006), the
molecular mechanisms that underlie de novo lumen formation are not yet known,
and await the further characterization of the mutants and identification of
the affected gene products. Interestingly, a recent study has shown that
integrin-talin complexes are necessary to maintain fine terminal tracheal
branches and their luminal organization during larval life
(Levi et al., 2006),
suggesting that not only tube formation but also tube maintenance is under
genetic control.
Do general cellular principles underlie branching morphogenesis in different organs?
As outlined above, genetic analysis combined with live imaging approaches have revealed many of the cellular activities that are intimately linked to branching morphogenesis during tracheal development in Drosophila. The process relies on directed cell migration, controlled cell rearrangement and cell intercalation, the secretion of apical matrices to help keep branch cells together and to help shape the luminal space, and the de novo formation of luminal space in distinct cell types. Several genes that play important roles in branching have been identified, and the molecular events that underlie these cellular activities are beginning to be worked out.
An obvious question to ask at this point is whether similar cellular
activities are involved in branching morphogenesis in other organisms (see
also Lu et al., 2006). In the
following section, we briefly discuss a few such similarities and
differences.
The organ that is most often compared to the developing Drosophila
tracheal system is the mammalian lung
(Cardoso and Lu, 2006;
Hogan and Kolodziej, 2002;
Warburton et al., 2005). The
finding that Fgf10 is expressed in a dynamic fashion at branch tips in the
mammlian lung and is intimately linked to the branching process has
highlighted that molecular similarities exist between branching in the
mammalian lung and the insect trachea
(Bellusci et al., 1997;
Sekine et al., 1999;
De Moerlooze et al., 2000).
However, it remains unclear which cellular activities are controlled by Fgf
signalling during lung budding. Although Fgf does affect cell proliferation at
the bud tips, it has been argued, based on studies of lung bud explants, that
these local changes in proliferation are not the triggering event that
initiates lung budding, indirectly implying that the control of cell migration
is a possible major player in branching
(Nogawa et al., 1998). Indeed,
Fgf can control cell migration in cultured mouse lung cells
(Park et al., 1998). In the
developing air sac in Drosophila, a branched organ that also grows
tremendously during the branching process due to cell division, two different
receptor tyrosine kinases, Egfr and Fgfr, have been linked to the control of
cell proliferation and cell migration, respectively
(Cabernard and Affolter, 2005)
(see Fig. 4). Maybe the
situation is somewhat similar in the developing lung buds. High-resolution
live imaging and local loss-of-function analysis (for example, by creating
chimeric mice; see below) will be necessary to address this issue in detail.
It is possible that very limited cell movement or displacement (rather than
extensive cell migration) induces an asymmetry in outgrowing buds that is
sufficient to control the spatial organization of branches.
An emerging model system for the study of organ branching is the developing
ureteric bud during mouse kidney development. The use of in vitro organ
culture and live imaging, in combination with the analysis of genetically
mosaic mouse kidneys, has begun to provide novel insights into the cellular
processes that drive renal branching morphogenesis
(Shakya et al., 2005)
(reviewed by Costantini,
2006). It has clearly been shown that the tips of the ureteric
buds are the growth centres. Similar to the lung, however, it remains to be
seen whether Gdnf, a growth factor intimately linked to ureteric branching,
controls the branching process via cell division or cell migration. It also
remains to be investigated whether controlled cell rearrangement and cell
intercalation, and whether the formation of apical matrices or the de novo
formation of luminal space in distinct cell types, are intimately linked to
certain stages of the branching process in the lung or ureteric bud. The same
considerations apply to other organs that undergo excessive branching, such as
the salivary gland or the mammary gland
(Tucker, 2007;
Lu et al., 2006;
Cardoso and Lu, 2006).
A rather astonishing number of similarities between the developing tracheal
system and the formation of blood vessels via angiogenesis have recently
emerged. The vertebrate vasculature is first assembled from scattered
endothelial precursor cells, and is then enlarged and remodelled by the
sprouting, splitting and regression of branches, which shape a hierarchical
vascular network that allows directional blood flow
(Carmeliet, 2003). Members of
the vascular endothelial growth factor (Vegf) family of signalling molecules
are key regulators of blood vessel formation and function, and act through
receptor tyrosine kinases of the Vgfr family
(Ferrara et al., 2003). In an
influential study, Gerhardt and colleagues have shown that Vegfa controls
angiogenic sprouting by guiding filopodial extensions from specialized
endothelial cells situated at the tip of vascular sprouts
(Gerhardt et al., 2003)
(Fig. 7). This is rather
similar to how neural growth cones and tracheal cells navigate through the
developing embryo. Further studies in different model systems, including in
mouse and zebrafish, have shown that the distinction between the leading tip
cell and the following stalk cells in growing angiogenic sprouts involves N
signalling via the Delta-like 4 (Dll4) ligand (reviewed by
Adams and Alitalo, 2007;
Gridley, 2007;
Roca and Adams, 2007). Reduced
levels of Dll4 or reduced N signalling enhances the number of tip cells in a
given branch, resulting in a dramatic increase in the sprouting of endothelial
tubes; conversely, increased N signalling reduces angiogenic sprouting by
inhibiting tip cell formation. Although the precise spatial regulation of N
signalling in angiogenic sprouts remains to be analysed, the molecular control
of the distinction between tip cells and stalk cells might be rather similar
in angiogenic sprouts and tracheal branches, in which the control of tip cell
formation is also linked to N-Dl signalling.
|
; Kamei and Weinstein,
2005; Suchting et al.,
2006). Similarly, Robo signalling has been involved in tracheal
pathfinding in the developing nerve cord in Drosophila
(Lundstrom et al., 2004).
Do stalk cells of endothelial sprouts and tracheal branches also show
similar cellular behaviour? Studies of tracheal cells have shown that stalk
cells do not divide during branch formation but rearrange excessively,
intercalate and form autocellular AJs in the fine branches of the trachea. The
lumen is present from the onset of branching, although it is restructured
during branch elongation. During the formation of the first angiogenic sprouts
in the zebrafish embryo, the intersegmental vessels (ISVs), the cellular
behaviour underlying the formation of a first, closed, vascular network has
been analysed in detail using live imaging approaches (reviewed by
Weinstein, 2002;
Lawson and Weinstein, 2002;
Childs et al., 2002;
Kamei et al., 2004). It was
discovered that during ISV formation, cells also rearrange extensively, but
that sprouting is accompanied by endothelial cell divisions
(Siekmann and Lawson, 2007;
Leslie et al., 2007;
Blum et al., 2008).
Intercalation processes that generate cells in a chain similar to those
observed in the fly tracheae have not been seen in the developing ISVs,
although they might occur in capillaries formed in other regions of the
embryo. It has initially been proposed that ISVs consist of three cells only,
arranged in a chain-like structure (Childs
et al., 2002), and that the lumen in this chain is established by
the intracellular and intercellular fusion of vacuoles, resulting in a largely
intracellular luminal space within the ISV network
(Kamei et al., 2006). More
recent studies suggest that more than three cells make up the ISVs, and that
most of the luminal space is in-between cells and so is largely extracellular
(Blum et al., 2008). Further
studies are necessary before a definitive comparison of the cellular
activities involved in ISV sprouting angiogenesis and tracheal branching can
be made.
One of the most striking similarities between the development of the
vertebrate vasculature and the tracheal system in Drosophila is the
involvement of branch fusion, an essential process without which a continuous,
functional tracheal or vascular network cannot be established. The fusion of
adjacent branches has to be highly regulated in time and space, and involves
de novo lumen formation processes. In the developing tracheal system, fusion
involves a highly specialized cell type, the fusion cell, which eventually
develops into a doughnut-like cell with two apical surfaces and a de novo
generated luminal space (see above) (see also
Uv et al., 2003). In the
developing vasculature, only a few studies have addressed how vessels fuse in
vivo (e.g. Blum et al., 2008),
and the cellular events remain poorly characterized. It will be interesting to
find out in future studies whether more similarities or differences are added
to the cellular activities that underlie branching in different organ
systems.
Conclusion
What do we expect to learn in the next few years with regard to branching morphogenesis, and how will greater insights into this fascinating biological process be achieved?
Morphological processes in many cases involve the generation of force and the subsequent reaction to such forces. Very little is known still about the exact nature of the forces that control cell behaviour during branch formation in the Drosophila tracheal system. Future studies have to address this issue. Both in angiogenesis and in tracheal branching, cell rearrangements are linked intimately to the branching process, and it remains to be investigated how cell-cell junctions deal with the requirement to be constantly remodelled while providing permanent tissue integrity. Proteins secreted into the luminal space have emerged as being important and essential regulators of network formation and of tube length and expansion control in the tracheal system. Are similar processes at work in branched organs in vertebrates? Are ZP proteins or chitin-like molecules involved? And, particularly with regard to the vertebrate vasculature and the invertebrate trachea, how are luminal spaces formed de novo, and how do branches fuse to establish integrated networks?
Live imaging will certainly play a key role in identifying the cellular activities linked to biological functions, and genetic analyses will have to provide evidence for the functional significance of molecular modules. The research approaches involved in trying to achieve a better understanding of branching morphogenesis have moved to cell biological analysis in vivo, and much progress can be expected in the near future from the integration of results obtained from cell biological studies in yeast and other systems with distinct cellular activities involved in organ formation in vivo.
Supplementary material
Supplementary material for this article is available at
http://dev.biologists.org/cgi/content/full/135/12/2055/DC1
ACKNOWLEDGMENTS
We thank Stefan Luschnig, Shigeo Hayashi, and the members of the Affolter lab for comments on the manuscript. Work in our laboratory is supported by the Kantons Basel-Stadt and Basel-Land, the Swiss National Science Foundation, KTI, EMBO, and by a Network of Excellence grant `Cells into Organs' from the FP6 of the European Community.
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Cat::GFP expression in the tracheal system, are shown in
parallel with (E) four sketches representing the same steps. (F)
The proteins involved in the genetic control of this process. (A-E) To better
understand the `topology' of the cells, the edges of two neighbour cells were
colored in red and green, respectively. (A) Pairing: tracheal cells are in a
side-by-side arrangement along the branch lumen. (B) Reaching around the
lumen: individual cells establish contact with themselves and start to form
the first autocellular AJs (arrowhead). (C) Zipping up: autocellular AJs
extend as the two cells, which were initially paired, change their respective
positions. (D) Termination: in order not to lose all intercellular AJs (and
thus the adhesion between neighbouring cells), the transformation of
intercellular AJs into autocellular AJs stops, with small intercellular AJ
loops connecting adjacent cells to each other. Adapted, with permission, from
Ribeiro et al. (Ribeiro et al.,
2004
