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First published online December 12, 2006
doi: 10.1242/10.1242/dev.02666
1 Departments of Physiology and Biochemistry, University of California, San
Francisco, Rock Hall, Room GD481, 1550 4th Street, San Francisco, CA 94143,
USA.
2 Howard Hughes Medical Institute, University of California, San Francisco, Rock
Hall, Room GD481, 1550 4th Street, San Francisco, CA 94143, USA.
Authors for correspondence (e-mail:
YuhNung.Jan{at}ucsf.edu;
wg2135{at}columbia.edu)
Accepted 28 September 2006
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SUMMARY |
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 TOP SUMMARY INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key words: Drosophila, Sensory map, Dendritic arborization neurons, Genetic screen, Axon targeting, Dendrite morphogenesis
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INTRODUCTION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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; Wong et al.,
2002). POU-domain transcription factors act to specify both
class-specific axon and dendrite morphology among groups of PNs, suggesting
that dendrite and axon morphogenesis can be regulated together by some of the
same molecules (Komiyama et al.,
2003). Coordination between dendritic and axonal morphology and
development within cells is likely to be a general feature of nervous system
wiring. A major challenge is therefore to understand how, in the context of
their distinct morphologies and cytoskeletons, dendrite and axon development
can be linked with cell identity to ensure proper wiring of the nervous
system.
The Drosophila dendritic arborization (da) sensory neurons provide
a suitable system in which to study neuronal morphogenesis. These cells are
positioned just below the transparent body wall in the peripheral nervous
system (PNS) and branch in two dimensions
(Bodmer and Jan, 1987), making
it possible to study the growth and branching of whole dendritic arbors in
vivo (Gao et al., 1999). The
patterns of dendritic branching of da neurons have been characterized
(Grueber et al., 2002;
Sweeney et al., 2002) and
based on branching morphology were grouped into four distinct classes
(Grueber et al., 2002). The
genetic programs that regulate the development and morphological
diversification of these arbors are beginning to be elucidated
(Brenman et al., 2001;
Gao et al., 2000a;
Grueber et al., 2003a;
Li et al., 2004;
Moore et al., 2002;
Sugimura et al., 2004;
Ye et al., 2004). As yet,
however, there is no evidence of the functional relevance of these diverse
dendritic morphologies. Establishing this connection would help to develop a
system for studies of morphological development in the context of dendrite and
circuit function, and perhaps allow investigations of the functional
consequences of alterations in morphology produced in various mutant
backgrounds.
If morphological and functional diversity are correlated, da neurons with
different dendritic morphologies might project axons to different regions of
the central nervous system (CNS) and thus present sensory information with
spatial divergence. Elucidating the sensory axon pattern might begin to reveal
the relationship between dendrite morphology and function, and also allow
studies of coordinated and distinct molecular control of axonogenesis and
dendritogenesis using this system. A subset of da neuron axons have been
labeled in embryos and larvae and shown to project primarily to ventral
regions of the neuropil, with a small subset of axons projecting more dorsally
(Merritt and Whitington, 1995;
Schrader and Merritt, 2000).
Here we show that the axons of da neurons in different dendritic classes have
distinct morphologies and organize into different layers in the CNS. To begin
to examine the molecular mechanisms responsible for the specific patterns of
da neuron axons and dendrites, we tested candidate genes and generated 3299
ethylmethanesulfonate (EMS)-induced lethal lines to screen axon and dendrite
morphology simultaneously with high resolution. Our anatomical data, along
with this collection of mutants, provide entry points for identifying novel
genes and pathways that function during neuronal morphogenesis.
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MATERIALS AND METHODS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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), (5) hsFLP; Sp/CyO;
UAS>CD2>mCD8::GFP (Wang et
al., 2004), (6) hsFLP; ppk-Gal4;
UAS>CD2>mCD8::GFP, (7) hsFLP;Gal4109(2)80;
UAS>CD2>mCD8::GFP, (8) Gal4109(2)80;
ppk-eGFP. Axon projections in embryos: (9) UAS-Kaede;
ppk-eGFP. Ectopic expression of Robo2 and Robo3: (10)
UAS-robo2 (Rajagopalan et al.,
2000), (11) UAS-robo3
(Rajagopalan et al., 2000),
(12) yw/w; UAS-robo2 or robo3/CyO; ppk-eGFP th st
FRT2A/TM6 Ubx y+, (13) yw, hsFLP; Gal4109(2)80,
UAS-mCD8::GFP; tubP-Gal80, FRT2A.
Generation of clones
MARCM (Lee and Luo, 1999)
clones were produced as previously described
(Grueber et al., 2002) by
mating stocks 1 and 2 or 12 and 13 above. FLP-out clones were produced by
providing a 30 minute heat shock (38°C) to late embryonic and early larval
progeny from matings of stocks 3 and 6 or 7 and 8 above.
Transgenic constructs
pickpocket (ppk)-Gal4 was constructed by replacing the
eGFP portion of ppk-eGFP
(Grueber et al., 2003b) with a
Gal4 fragment. The Gal4 fragment was initially digested from
pPTGAL (Sharma et al., 2002)
as a HindIII fragment and was subsequently cloned into the
HindIII site of pBlueScript (Stratagene). The final ppk-Gal4
construct was produced by performing a three-way ligation using: (1) the
ppk promoter released from ppk-eGFP as an
EcoRI-KpnI fragment; (2) Gal4 released from
pBlueScript-Gal4 as a KpnI-XbaI fragment; and (3)
pCasper vector released from pCasper hs-43 lacZ digested with
EcoRI and XbaI.
To generate pUAST-Kaede, Kaede cDNA
(Ando et al., 2002) was excised
from pCS2+-Kaede (courtesy of Dr A. Miyawaki) at the BamHI
and EcoRI sites and then ligated into pCDNA3.1 (Invitrogen, Carlsbad,
California). It was subsequently excised from pCDNA3.1 and ligated into
pUAST at KpnI and XbaI sites.
Immunohistochemistry and image analysis
Immunostaining and mounting of larvae harboring MARCM clones was performed
as previously described (Grueber et al.,
2002; Lee and Luo,
1999). Animals with FLP-out clones were processed similarly, and
immunolabeled with rabbit-anti-GFP (1:2000; kindly provided by Dr Yang Hong,
UCSF), mouse anti-CD2 (1:200; Serotec, Raleigh, NC), and rat anti-mCD8 (1:100;
Caltag/Invitrogen, Carlsbad, CA), and in some cases mouse anti-Fas II
(Developmental Studies Hybridoma Bank, University of Iowa). Secondary
antibodies used were Cy2-conjugated donkey anti-rabbit, Rhodamine Red
X-conjugated donkey anti-mouse, and Cy5-conjugated donkey anti-rat all at
1:200 dilution (Jackson ImmunoResearch, West Grove, PA). Immunostained larvae
were imaged on a TCS SP2 confocal microscope (Leica Microsystems, Bannockburn,
IL), or a Zeiss 510 Meta (Carl Zeiss Inc., Thornwood, NY). Live imaging of
mutant embryos was performed on an MRC-600 confocal microscope (Bio-Rad,
Hercules, CA). Ortho views were created using LSM510 software (Carl Zeiss
Inc.).
Mutagenesis
Males were fed 0.025 mol/l EMS in 1% sucrose solution according to a
modified method from Lewis and Bacher
(Lewis and Bacher, 1968).
Mutations were mapped by standard recombination mapping using the multiply
marked ru h th st cu sr e ca line, followed by deficiency mapping and
complementation analysis with known mutant alleles.
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RESULTS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). The
cell bodies are distributed in ventral, ventral', lateral and dorsal
clusters between the epidermis and muscles, spreading dendrites across the
body wall, and axons to the ventral nerve cord
(Fig. 1A). We reasoned that if
morphological classes correspond to at least partially distinct sensory
systems, then their axons may have divergent morphologies and target
non-overlapping regions of the ventral nerve cord, where information will be
relayed to second-order neurons. Previous studies have found that most da
neurons arborize together in a common fascicle in the ventral CNS, with a
subset, including at least some class I da neurons, projecting to more dorsal
neuropil (Merritt and Whitington,
1995; Schrader and Merritt,
2000). In light of studies showing distinct morphological types of
da neurons, we used mosaic analysis with a repressible cell marker (MARCM)
(Lee and Luo, 1999) to examine
the morphology of da neuron dendrites and axons in third instar larvae. As a
MARCM driver we used Gal4109(2)80
(Gao et al., 1999), which
labels all multidendritic (md) sensory neurons, including those belonging to
the da subgroup (Fig. 1B).
Owing to the sparse labeling of central neurons, the 109(2)80 driver
combined with MARCM allowed us to resolve axon morphology of individual
neurons (Fig. 1B). We collected data from wild-type da neuron clones in segments A2-A7 to identify their axon projections in the CNS (n=128). Different da classes showed distinctive types of central projections. Class I neurons were unique in their projection to the dorsal neuropil (see below; n=19). Class II axons showed collateral branches (branches exiting from the main axonal trunk, although the timing of their emergence has not been determined) that were not observed in class III and IV neurons (Fig. 1C; n=27). The class I neuron vpda also showed such a branch (Fig. 1C). Class IV neurons projected axon branches across the midline, but these were only rarely observed for the other classes (Fig. 1C; n=39; we observed one case in which the v'pda class III neuron crossed the midline). Dorsal and ventral' class IV axons crossed the midline, but axons from the ventral neuron did not. Each class IV neuron also showed a large accumulation of branches medial to the commissural/longitudinal branch bifurcation (Fig. 1C). The class III terminals extended in an anteroposterior (AP) orientation and were relatively unbranched, showing neither the collateral branches observed in class II neurons, nor contralateral projections observed among class IV neurons (Fig. 1C; n=43).
The axons of class I and class IV neurons also showed evidence of
somatotopic arrangements in the CNS. The trajectory of class I neurons in the
CNS mirrored the polarity of their dendrites in the periphery. Dorsal class I
neurons have distinct polarity with respect to the AP body axis: dendrites of
ddaD extend anteriorly and dendrites of ddaE extend posteriorly
(Grueber et al., 2002).
Likewise, we found that the ddaD axons extended anteriorly in the CNS, whereas
the ddaE axons extended posteriorly (Fig.
1C). Among the class IV neurons, only neurons positioned in the
dorsal and ventral regions of the body wall, but not the lateral region,
extended axons across the midline (Fig.
1C), fitting with principles of somatotopy established for body
wall bristle neurons (Levine et al.,
1985; Merritt and Whitington,
1995). These data together demonstrate that da neuron classes have
distinguishing axon terminals, and that neurons in the same class show
evidence of somatotopic organization.
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;
Pfluger et al., 1988).
Fasciclin II-labeled axon tracts provide a frame of reference for assessing
dorsoventral (DV) position in the CNS
(Landgraf et al., 2003)
(Fig. 2A). We studied the DV
positions of axons in 42 ventral nerve cords (VNCs) using MARCM, and 18 VNCs
using the FLP-out system (Basler and
Struhl, 1994; Wang et al.,
2004; Wong et al.,
2002). Both techniques revealed that each class I neuron extended
axons to dorsal regions of the neuropil, terminating just lateral to the
dorsomedial (DM) fascicle (Fig.
2B). The position of class I axons was therefore indistinguishable
at this level of resolution from the position of the dbd terminal arbor (see
Fig. 2D,E)
(Zlatic et al., 2003),
implying that information from class I neurons and the putative
stretch-sensing dbd neuron might be processed similarly in the CNS. Class II,
III and IV axons targeted the ventral CNS without obvious class-specific
dorsoventral lamination of terminal position
(Fig. 2C-E). The positions of
the class II collateral branches were somewhat variable, either terminating on
the ventrolateral (VL) fascicle (Fig.
2C), or slightly lateral to VL (vdaA often had a more lateral
termination; data not shown). These data together provided anatomical support
for distinct functions among different da neurons, fitting with their distinct
dendritic arbor morphologies. Class II, III and IV axons project similarly to
known tactile afferents, while class I neurons have projections like known
proprioceptive or strain-sensing neurons.
Mediolateral lamination of axon terminals
We next examined whether the terminal positions of the ventral-projecting
class II, III and IV neurons could be further distinguished by their position.
Short pickpocket (ppk) enhancer sequences can drive gene
expression strongly in all class IV neurons and weakly in class III neurons
(Grueber et al., 2003b).
Viewing all class IV neurons together revealed that they crossed the midline
in a single fascicle, that the stereotyped branching at the
commissural-longitudinal junction overlapped for all neurons, and that
longitudinal projections were not always tightly fasciculated
(Fig. 3A,
Fig. 5B). In ppk-eGFP
and ppk-Gal4, UAS-CD8::GFP animals, we observed a strongly labeled
set of medial axons and a weakly labeled, slightly more lateral, layer of
terminals (Fig. 3A). We
suspected that the weakly labeled axons were class III axons, which may form a
layer next to class IV axons. To test this idea, we introduced
ppk-Gal4 into the FLP-out mosaic system. We examined the relative
locations of all class III axons except ddaF (whose axon was labeled too
weakly) and found that their major longitudinal projections terminated
immediately lateral to the scaffold of class IV axons
(Fig. 3B).
The ppk reporter lines alone do not label the class II axons, and thus did not allow us to determine whether all da classes form a laminar organization or only the class III and IV neurons. However, examination of FLP-out clones produced with Gal4109(2)80, with or without ppk-eGFP to label class IV neurons, permitted labeling of different axon groups. We found that class II neurons with a significant longitudinal projection formed a third layer of sensory axons that was lateral to both class III (Fig. 3C) and class IV axons (Fig. 3D), with class II collateral branches terminating in a distinct, even more lateral, position (Fig. 2C).
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Embryonic formation of the laminar pattern
The above FLP-out and MARCM data were collected from third instar larval
stages, so we next examined when during development we could observe layering
of the different classes of axons. To achieve live two-color discrimination of
different neuronal classes in embryonic and early larval stages we generated
transgenic flies expressing a photoconvertible fluorescent protein, Kaede
(Ando et al., 2002), and placed
expression under the control of Gal4109(2)80 in the
presence of ppk-eGFP (Fig.
4A,A'). We converted the Kaede protein from green to red
fluorescence using a 10-30 second UV pulse and examined the position of all da
axons relative to ppk-eGFP-labeled class IV axons. As early as the
sensory axon scaffold could be visualized (stage 17), class IV axons occupied
a medialmost layer with respect to other classes
(Fig. 4B,C). These data
indicate that a laminar pattern develops at least by late embryonic stages and
is maintained without qualitative change in larvae.
Alteration in md neuron axon morphology by Robo family members
Our anatomical data revealed several features of da neuron axon projections
that correlated with previously described dendritic classes, including
mediolateral position, midline crossing, presence or absence of collateral
branches, and relative position in the DV axis. Because of the role of Robo
receptors in specifying longitudinal position in the VNC
(Simpson et al., 2000;
Rajagopalan et al., 2000;
Zlatic et al., 2003), we
examined the possible functions of these genes in sensory axons. Loss of
either Robo, Robo2 or Robo3 caused severe (Robo) or mild (Robos 2 and 3)
alteration in sensory axon morphology (Fig.
5A). Due to the widespread regulation of VNC patterning by Robo
family members (Rajagopalan et al.,
2000; Simpson et al.,
2000) these defects could arise by autonomous or non-autonomous
regulation of sensory arbor morphology. We found that misexpression of Robo3,
but not Robo2, under the control of Gal4109(2)80 induced
axon mistargeting and ectopic branching of class IV axons primarily along the
VL fascicle (Fig. 5B), the
normal position of collaterals of class II axons
(Fig. 2C). MARCM-based
overexpression of Robo3 indicated that this branching phenotype was cell
autonomous (90%; n=20; Fig.
5C). Furthermore, class III neurons showed ectopic collateral
branching (86%; n=14; Fig.
5C), and class II axons either truncated at the approximate
location of their normal collateral branches, or turned from a more medial
position and projected laterally to outer neuropil (60%; n=10;
Fig. 5C). Neither Robo2 nor
Robo3 overexpression under the control of Gal4109(2)80
caused obvious shifts of the relative laminar position of da axon terminals
(Fig. 5C). Robo3-overexpressing
class III axons occasionally (21%; n=14) extended longitudinal
branches that were separated from the class IV scaffold by a gap, which could
indicate a shift to an outer layer. We next examined the distribution of Robo3
protein in the PNS. Expression was observed in chordotonal organs, as
previously described (Zlatic et al.,
2003), and weakly in other cells in the periphery (data not
shown). We could not resolve a class-specific expression in the md neurons,
but also cannot exclude low-level expression in some of these cells. Together,
these results support the view that Robo family members can regulate sensory
axon morphology and can modify class-specific features of md arbors
(Zlatic et al., 2003).
Furthermore, although a Robo code may regulate the broad location of sensory
arbors, it appears not to determine the laminar pattern of the different da
classes alone.
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) and in
l(3)10363 to protein tyrosine phosphatase 69D (Desai et al., 1996).
The cell autonomy of these mutant phenotypes and other lines has yet to be
fully characterized. We also isolated a complementation group consisting of
four alleles that we named baobab (boa) for the frequent
inverted class IV axon thickenings (Fig.
6N-O). Dendrites were not disrupted in boa mutants
(Fig. 6P). Labeling of the
boa axon scaffold with BP102 revealed weakly labeled longitudinal and
commissural tracts, suggesting that this mutation may generally affect axon
development (Fig. 6Q). Given that class IV axons usually terminate in a tract next to class III and II axons, further mosaic studies of mutations in which class IV axons are severely unbundled or laterally displaced might provide insight into the development of axon patterning. We suspect that the high sensitivity of our screen will allow the identification and characterization of genes not previously implicated in neuronal morphogenesis.
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DISCUSSION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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).
Visual systems retain a map of sensory position in their central axonal
projections. The axons of olfactory receptor neurons project to similar
positions in the brain if they express the same odorant receptor, and thus
transform information about stimulus quality into a spatial map
(Gao et al., 2000b;
Vosshall et al., 2000).
Gustatory projections retain aspects of both stimulus location and quality in
their map (Wang et al.,
2004).
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). How is information from this predominant body wall sensory
system represented in the CNS and what might this organization tell us about
the possible functions of da neurons? We show that neurons with different
dendritic branching morphologies target distinct regions of the CNS,
supporting the existence of a modality map of da neuron axons. We further
provide evidence for nested somatotopic mapping in class I and class IV da
neurons. Individual class I neurons extend their dendritic and axonal arbors
in the same preferred direction along the AP body axis
(Fig. 1C). Class IV axons
project across the midline according to the cell body position along the DV
axis of the body wall, with dorsal and ventral cells, but not more lateral
cells, crossing the midline. It is possible that class II and III neurons also
project in a somatotopic pattern that was not uncovered by our analysis. Thus,
da neuron connectivity appears to incorporate both class and position-specific
components, with some apparent correlations with dendritic field
orientation.
In the context of sensory processing, these data suggest distinct functions
for different morphological classes of da neurons. The class II-IV neurons
target a ventral region of the neuropil; thus information from these neurons
might be processed similarly to ventral-projecting tactile sensory bristle
neurons (Schrader and Merritt,
2000). Within this ventral region, the class-specific laminar
pattern could allow differential connectivity with second-order interneurons.
Additionally, class II neurons, with their collateral branches, might provide
information to distinct central circuits. The class I neurons targeted a more
dorsal region of the neuropil, which is generally a characteristic of
proprioceptive afferents in insects
(Merritt and Murphey, 1992;
Murphey et al., 1989;
Pfluger et al., 1988;
Schrader and Merritt, 2000).
Indeed, a class of da neurons in Manduca has been shown to target
dorsal neuropil, and to respond to stretch of the cuticle
(Grueber et al., 2001). Many
insect proprioceptors, including chordotonal organs and the bipolar dendrite
neurons, have dendrites oriented in a preferential direction relative to the
body axis. Notably, the primary dendrites of each class I neuron are oriented
dorsally and secondary dendrites are oriented anteriorly and posteriorly
(Grueber et al., 2002). This
arrangement could allow larvae to compare distension along major body axes.
While the anatomical arrangement of their axons suggests distinct functions
for different da neurons, dissecting these different functions will ultimately
require behavioral and physiological studies
(Ainsley et al., 2003;
Liu et al., 2003;
Tracey et al., 2003).
Mechanisms of class-specific axon and dendrite patterning
A notable feature of the mapping of da sensory afferents is their
predominant organization into class-correlated mediolateral layers (Figs
2,
3), with class IV neurons in a
medial layer, class III neurons intermediate, and class II neurons most
lateral. These layers do not correspond to the medial, intermediate and
lateral fascicles that have their position specified by a Robo combinatorial
code (Rajagopalan et al.,
2000; Simpson et al.,
2000); thus novel molecular cues may contribute to this laminar
organization. Indeed, it has been postulated that the Robo code provides
information about the broad zone that a growth cone targets, while a
complementary fasciculation code fine-tunes pathway choice within that zone
(Rajagopalan et al., 2000). It
is conceivable that Robo proteins could participate in specifying the lateral
position of collateral branches, as Robo3 overexpression in individual neurons
induced ectopic branching from the axon shaft. Although we did not detect
cell-type-specific expression of Robo3 in neurons that normally show such
branching, it is notable that Robo3 has been implicated in cell-type-specific
patterning decisions of PNS axons (Zlatic
et al., 2003), and that Slit2 has been proposed as a positive
regulator of collateral branching of dorsal root ganglion sensory axons
(Wang et al., 1999).
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), and dendrites of da neurons engage in
class-selective interactions during development to ensure their proper spacing
(Grueber et al., 2003b;
Sugimura et al., 2003). It is
therefore conceivable that intraclass and interclass interactions could
participate in the sorting of somatosensory axons. Axons from different
classes could also project to specific layers that are prepatterned by the
processes of target interneurons or by other axons. Finally, the projection of
da axons to different layers could conceivably reflect a temporal order of
sensory axon arrival in the CNS, similar to the three-way correlation between
mediolateral axon position, physiological function and time of differentiation
among Drosophila wing campaniform sensilla
(Palka et al., 1986). Among
the ventral cluster da neurons, a group with differentiation that has been
examined in the greatest detail, the class II neurons appear to be the
first-born, followed by class III neurons and class IV neurons
(Orgogozo et al., 2001). These
data suggest a possible correlation between birth order and axon position in
the neuropil, although additional early markers of da neurons and further
high-resolution imaging studies are required to further test this
scenario.
The molecular basis for insect sensory neuron differentiation, as well as
anatomical studies of somatosensory axon mapping and VNC circuitry, have been
subjects of considerable study (Blagburn
and Bacon, 2004), and principles are emerging that link the two
areas into molecular models of connectivity and synaptic specificity
(Merritt et al., 1993;
Merritt and Whitington, 1995;
Nottebohm et al., 1992;
Zlatic et al., 2003). Among
embryonic sensory neurons in Drosophila, there is a three-way
correlation between soma position, proneural transcription factor expression
and axon projection pattern, suggesting that these transcription factors may
endow aspects of modality-specific axonal projections
(Merritt and Whitington,
1995). Such a link was recently established between
chordotonal-organ-specific expression of the atonal proneural gene
and expression of the Robo3 axon guidance molecule in these same organs
(Zlatic et al., 2003).
Misexpression experiments with atonal, robo3 and comm
suggest a model whereby Atonal activates expression of Robo3, which in turn
specifies mediolateral positioning in chordotonal versus bipolar dendrite-type
axon projections (Zlatic et al.,
2003). These studies provide an important basis for understanding
the establishment of sensory circuitry in the VNC.
To begin to address the molecular basis of axon and dendrite patterning
using the anatomical framework established for the da neurons, we undertook a
forward genetic approach, which has proven a successful means to identify
regulators of neuronal morphogenesis (Gao
et al., 1999; Lee et al.,
2000; Reuter et al.,
2003). A strength of this screen was the ability to simultaneously
assess phenotypes in dendrites and axons at the level of single identifiable
neurons. We have identified numerous complementation groups that affect axon
patterning, including several mutations with a molecular nature as yet unknown
(see Table 1). These mutations
should allow us to identify new genes involved in axon morphogenesis and place
these into the context of their effects on somatosensory axon patterning and
circuitry. Given that we further identified many mutations affecting dendrite
morphogenesis (Table 1), we
expect that studies of the mutations identified from the screen will also
allow us to address the similarities and distinctions between axon and
dendrite development.
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ACKNOWLEDGMENTS |
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Footnotes |
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