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Developmental functions of the Distal-less/Dlx homeobox genes

¹ Department of Anatomy, University of Wisconsin, Madison, WI 53706, USA
² Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, University of California at San Francisco, San Francisco, CA 94143-0984, USA

View larger version (33K): [in a new window]   Fig. 1. Expression and phenotypes of Dll in the Drosophila antenna and leg. (A) Wild-type adult Drosophila antenna. The arista (ar) vibrates in response to sound, putting torque on the third antennal segment (a3), which then rotates. A large chordotonal organ, the Johnston’s organ, inside the second antennal segment (a2) processes and transmits auditory information via the antennal nerve through the first antennal segment (a1) to the brain. The antenna also serves as a major olfactory organ. a3 is covered with olfactory sensilla. (B) Dll expression, visualized via use of a ß-galactosidase-encoding enhancer trap, in a late pupal antenna. Dll is expressed from distal a2 through the arista. (C) A weak combination of hypomorphic Dll alleles results in antenna toward leg transformations. Distal a3 and the proximal part of the arista are transformed to medial leg structures. (D) Wild-type adult Drosophila leg. The proximal-most coxa (cx) and distal-most claws (cl) are indicated. tr, trochanter; fe, femur; ti, tibia; t1-t5, first to fifth tarsal segments. (E) Dll expression, visualized via use of a ß-galactosidase-encoding enhancer trap, in a late pupal leg. Dll is expressed in the distal trochanter, weakly in the tibia, and in the tarsal segments. (F) A weak combination of hypomorphic Dll alleles results in truncation of distal leg structures.

View larger version (57K): [in a new window]   Fig. 2. Expression of Dll in the embryonic Drosophila brain. Dorsal view of a late stage Drosophila embryo stained for Dll (green), the glial marker RK2 (red) and the axonal marker Fasciclin 2 (blue). (A) Low-magnification view of entire embryo with the two lobes of the brain indicated by arrows. (B,B') High magnification views of the brain where Dll is expressed in neurons (n) in the brain, as well as some of the glia lining a transverse axon commissure. These glia, indicated by arrowheads, also express RK2 and therefore are yellow in B.

View larger version (41K): [in a new window]   Fig. 3. Expression of Dll in embryonic Drosophila limb primordia. Lateral views of stage 11 (A) and 15 (B) Drosophila embryos stained for Dll (green) and Escargot (Esg; red) protein. Anterior is towards the left. Esg is expressed in imaginal tissues that ultimately give rise to adult structures. Dll is expressed in the first to third thoracic segments (T1-T3) in clusters of cells that give rise to both the leg imaginal discs and the larval Keilin’s organs. Dll also is expressed in the precursors of the labral (lr), antennal (an), maxillary (mx) and labial (la) larval sense organs. At stage 15, Dll is expressed in some brain (br) precursors, but appears not to be expressed in head imaginal tissues. The wing (w) and haltere (h) discs express Esg, but not Dll.

View larger version (36K): [in a new window]   Fig. 4. Expression domains of Dlx1, Dlx2, Dlx5 and Dlx6 during mouse brain development. (Top) Schema of a transverse section through the E12.5 mouse telencephalon showing the combined expression of Dlx transcripts. Most cells in the subpallial telencephalon express Dlx1, Dlx2, Dlx5 or Dlx6 at some stage of their differentiation. The arrows indicate the migration from the subpallium to the pallium (cortex) (Marin and Rubenstein, 2001a). The boxed region on the left is used in the middle section to show the expression of Dlx2, Dlx1, Dlx5 and Dlx6. Dlx2 is primarily expressed in undifferentiated cells; it is expressed in scattered cells in the ventricular zone (green dots), in most cells in the subventricular zone (uniform green) and in scattered cells in the mantle zone (green dots). Dlx6 is primarily expressed in differentiated cells in the mantle zone (uniform peach). Dlx1 (red) and Dlx5 (blue) are expressed in intermediate patterns. (Bottom) A hypothesized genetic and biochemical pathway that proposes the sequential role of Dlx2, Dlx1, Dlx5 and Dlx6 at different stages of differentiation. Telencephalic regions are as follows. Pallium: neocortex (NCX) and palliocortex (PCX). Subpallium: lateral ganglionic eminence (LGE). Medial ganglionic eminence (MGE). Stages of differentiation: ventricular zone (VZ); subventricular zone (SVZ); mantle zone (MZ). LV, lateral ventricle (ventricle of telencephalon); III, third ventricle (ventricle of the diencephalon).

View larger version (41K): [in a new window]   Fig. 5. Expression of three type A Dlx genes (Dlx2, Dlx5 and Dlx3; A-C) and one type B Dlx gene (Dlx1; D) in E10.5 mouse embryos shown by whole-mount in situ hybridization. The top pictures show a lateral view of the entire embryo (A-D); the bottom pictures show frontal views of dissected branchial arches. Expression of the Dlx genes is absent from the medial-most regions (these regions are under the control of the Msx and other genes). (E) Schematic lateral view of an E10.5 mouse embryo, highlighting craniofacial primordia that are under the control of the Dlx genes: the jaw, otic and olfactory apparatus (the branchial arches, otic vesicle and olfactory placode, respectively). The color wheel in the bottom right corner defines colors that correspond to the expression of type A Dlx genes: Dlx2, Dlx3 and Dlx5. These colors are used in the schema to describe the expression of these genes in the ectomesenchyme of the branchial arches and the ectoderm of the olfactory placode/pit and otic vesicle, respectively.

View larger version (49K): [in a new window]   Fig. 6. Alignments of various Dll and Dlx subdomains. (A) Dll/Dlx homedomain alignments. The consensus represents amino acids conserved among all family members. Dots in the consensus represent non-conserved residues. (B) Extended homedomain alignments of Dll and Dlx proteins. Underlined residues are conserved among two or more Dlx subgroup members or between Dll and Dlx. The consensi represent residues conserved in two or more subgroup members. Dots in the individual amino acid sequences represent gaps introduced to enhance the alignment. Dots in the consensi represent non-conserved residues. Asterisks denote human sequences. (C) Dlx2, Dlx3 and Dlx5 contain DllA domains. This domain originally was defined for various vertebrate Dlx3 proteins (Akimenko et al., 1994; Robinson and Mahon, 1994). Underlined residues are conserved between at least two Dlx proteins. The consensus represents residues conserved in two or more Dlx proteins. Dots represent non-conserved residues. (D) Sequences surrounding the conserved C-terminal tryptophan residues are also partially conserved. Underlined residues are conserved among two or more Dlx subgroup members or between Dll and Dlx. The consensi represent residues conserved in two or more subgroup members. (E) A conserved motif is found upstream of the Dll homeodomain and downstream of the Dlx2 homeodomain. (F) An spp motif is found upstream of the first conserved tryptophan. Underlined residues are conserved among two or more family members. Bold text is used to highlight the abundant serines and prolines.

View larger version (31K): [in a new window]   Fig. 7. Native Dlx binding sites. (A) Dlx1, Dlx2 and Dlx5 binding sites in the Dlx5/Dlx6 intergenic region (Zerucha et al., 2000). (B) Dlx2 binding site in Wnt1 (Iler et al., 1995). This interaction occurs predominantly via HBS-1 and the result is repression, not activation. (C) Xenopus Dlx3-binding site in human profilaggrin promoter (Morasso et al., 1996). (D) Dlx3-binding site in gene encoding the alpha subunit of human chorionic gonadotropin (Roberson et al., 2001). (E) Dlx5-binding site in collagen 1A1 (Dodig et al., 1996). (F) Dlx5 binding site in osteocalcin (Ryoo et al., 1997). (G) Dlx5-binding site in bone sialoprotein (Benson et al., 2000). We note that in several of these native binding sites, there are pairs of 5'-TAATT-3' sequences on opposite strands, and propose that these might bind Dlx dimers. Intriguingly, in vivo site selection with Dlx3 recovered opposing 5'-TAATT-3' sequences in 17/30 selected sites (Feledy et al., 1999b). We also note that the WIP sequence, which mediates repression by Dlx2, and OC-Box 1, which initially was reported to mediate repression, have 5'-CAAT-3' instead of 5'-TAATT-3' opposing a 5'-TAATT-3'.

View larger version (15K): [in a new window]   Fig. 8. Possible evolution of the Dll and Dlx genes and their functions. Modified from Panganiban et al. (Panganiban et al., 1997). The ancestral Dll gene may have functioned first in the developing nervous system, acquiring roles in appendage development later in evolution. Dll was duplicated multiple times in the deuterostome lineage to give rise to the present day six Dlx genes in mice and humans and the eight Dlx genes in zebrafish. See text for details. Not shown is the acquisition of Dll/Dlx functions in other tissues, including the branchial arches, the otic and olfactory systems, and hematopoietic system. It is not yet known when these roles were acquired or whether they predate the divergence of the protostomes and deuterostomes.