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PubMed1990

Expression of the homeobox Chick-en gene in chick/quail chimeras with inverted mes-metencephalic grafts.

The homeobox gene Chick-en, sharing homologies to the engrailed gene of Drosophila, is expressed, during early steps of development, in a restricted area of the chick embryo including mes-metencephalic neuroepithelia. The expression of the Chick-en gene has been analyzed in chick/quail chimeric embryos in which a portion of the 2-day-old mes-metencephalic neuroepithelium has been transplanted in an inverted position. By means of a monoclonal antibody, "Mab 4D9," recognizing engrailed proteins, it is shown that the expression of the Chick-en gene is regulated in the inverted neuroepithelium according to its new position in the host neural tube. The regulation takes place within 20 hr after transplantation. These results, together with previous data demonstrating that the phenotypic expression of the inverted neuroepithelium depends, also, on its new position in the host neural tube, strongly suggest that the engrailed protein could play an important role in the positional specification of the mes-metencephalic neuroepithelium.

Animals↗

PubMed1997

Homology modeling using simulated annealing of restrained molecular dynamics and conformational search calculations with CONGEN: application in predicting the three-dimensional structure of murine homeodomain Msx-1.

We have developed an automatic approach for homology modeling using restrained molecular dynamics and simulated annealing procedures, together with conformational search algorithms available in the molecular mechanics program CONGEN (Bruccoleri RE, Karplus M, 1987, Biopolymers 26:137-168). The accuracy of the method is validated by "predicting" structures of two homeodomain proteins with known three-dimensional structures, and then applied to predict the three-dimensional structure of the homeodomain of the murine Msx-1 transcription factor. Regions of the unknown protein structure that are highly homologous to the known template structure are constrained by "homology distance constraints," whereas the conformations of nonhomologous regions of the unknown protein are defined only by the potential energy function. A full energy function (excluding explicit solvent) is employed to ensure that the calculated structures have good conformational energies and are physically reasonable. As in NMR structure determinations, information on the consistency of the structure prediction is obtained by superposition of the resulting family of protein structures. In this paper, our homology modeling algorithm is described and compared with related homology modeling methods using spatial constraints derived from the structures of homologous proteins. The software is then used to predict the DNA-bound structures of three homeodomain proteins from the X-ray crystal structure of the engrailed homeodomain protein (Kissinger CR et al., 1990, Cell 63:579-590). The resulting backbone and side-chain conformations of the modeled yeast Mat alpha 2 and D. melanogaster Antennapedia homeodomains are excellent matches to the corresponding published X-ray crystal (Wolberger C et al., 1991, Cell 67:517-528) and NMR (Billeter M et al., 1993, J Mol Biol 234:1084-1097) structures, respectively. Examination of these structures of Msx-1 reveals a network of highly conserved surface salt bridges that are proposed to play a role in regulating protein-protein interactions of homeodomains in transcription complexes.

Algorithms↗

PubMed1994

An invariant asparagine in the POU-specific homeodomain regulates the specificity of the Oct-2 POU motif.

The homeodomain defines a family of transcription factors broadly involved in the regulation of gene expression. DNA recognition, as observed in three representative complexes (Engrailed, Antennapedia, and MAT alpha 2), is mediated in the major groove by a helix-turn-helix (HTH) element and in the minor groove by an N-terminal arm. The three complexes share similar overall features, but they also exhibit significant differences in DNA interactions. Because these differences may distinguish the biological activities of different classes of homeodomains, we have investigated the contribution of the Oct-2 POU-specific homeodomain (POUHD) to the specificity of the bipartite POU motif. Comparative studies of variant protein-DNA complexes demonstrate the following. (i) Mutations in an invariant residue in the POUHD HTH (N347; residue 10 of the putative recognition alpha-helix) reduce octamer binding with the relaxation of specificity at one position (5'-ATGCAAAT). The inferred HTH side chain-base interaction, although not observed in the solution structure of the Antennapedia complex, is in accord with homologous contacts in the Engrailed and MAT alpha 2 cocrystal structures. (ii) Comparison of the DNA-binding properties of POU and POUHD demonstrates that POUs and POUHD independently regulate specificity at opposite ends of the DNA site (5'-TATGCAAAT). Both domains contact the two central bases (5'-TATGCAAAT) where coordinate binding of POUS in the major groove overrides the intrinsic specificity of POUHD in the minor groove. (iii) The differential sensitivity of POU and POUHD to 2'-deoxyinosine substitutions (a minor-groove modification) suggests that POUS binding repositions the POUHD N-terminal "arm".(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗

PubMed1994

Structural studies of the engrailed homeodomain.

The structure of the Drosophila engrailed homeodomain has been solved by molecular replacement and refined to an R-factor of 19.7% at a resolution of 2.1 A. This structure offers a high-resolution view of an important family of DNA-binding proteins and allows comparison to the structure of the same protein bound to DNA. The most significant difference between the current structure and that of the 2.8-A engrailed-DNA complex is the close packing of an extended strand against the rest of the protein in the unbound protein. Structural features of the protein not previously noted include a "herringbone" packing of 4 aromatic residues in the core of the protein and an extensive network of salt bridges that covers much of the helix 1-helix 2 surface. Other features that may play a role in stabilizing the native state include the interaction of buried carbonyl oxygen atoms with the edge of Phe 49 and a bias toward statistically preferred side-chain dihedral angles. There is substantial disorder at both ends of the 61 amino acid protein. A 51-amino acid variant of engrailed (residues 6-56) was synthesized and shown by CD and thermal denaturation studies to be structurally and thermodynamically similar to the full-length domain.

Amino Acid Sequence↗

PubMed1994

Differential DNA-binding specificity of the engrailed homeodomain: the role of residue 50.

To assess the importance of residue 50 in determining the binding specificity of the homeodomain from the engrailed transcription factor of Drosophila, the DNA-binding properties of isolated homeodomains containing glutamine (wild type), alanine, and lysine at this position have been studied. In binding site selection experiments using the wild-type engrailed homeodomain, TAATTA was identified as a high-affinity, consensus binding site. When the glutamine at position 50 was replaced by a lysine (QK50), the binding site preference changed to TAATCC. The half-life and affinity of the complex between the QK50 protein and a DNA site containing TAATCC were increased significantly compared to the half-life and affinity of the complex between the wild-type protein and a TAATTA site. This suggests that Lys50 forms a more favorable interaction with the TAATCC DNA than Gln50 does with the TAATTA site. In fact, the wild-type Gln50 side chain (which forms a hydrophobic interaction with the last A:T base pair of the TAATTA site in the cocrystal structure [Kissinger, C. R., Liu, B., Martin-Blanco, E., Kornberg, T. B., & Pabo, C. O. (1990) Cell 63, 579-590]) appears to play only a small role in determining binding affinity and specificity for the TAATTA site, as the QA50 mutant has only a 2-fold reduced affinity for the TAATTA site and discriminates between the TAATTA and TAATCC sites as well as the wild-type protein. As a result, determinants in addition to Gln50 must be involved in establishing the differential binding specificity of the engrailed homeodomain.

Amino Acid Sequence↗

PubMed1994

Nuclear magnetic resonance solution structure of the fushi tarazu homeodomain from Drosophila and comparison with the Antennapedia homeodomain.

The three-dimensional structure of a recombinant 70-residue polypeptide containing the complete fushi tarazu (ftz) homeodomain from Drosophila melanogaster has been determined by nuclear magnetic resonance (NMR) spectroscopy in solution. On the basis of 915 upper distance constraints derived from nuclear Overhauser effects and 178 dihedral angle constraints, a group of 20 conformers representing the solution structure of the ftz homeodomain was computed with the program DIANA and energy-minimized with the program OPAL. The average of the pairwise root-mean-square deviations of the individual NMR conformers relative to the mean coordinates is 0.50 A for the backbone atoms N, C alpha and C' of residues 8 to 53. The molecular architecture includes three helices comprising the residues 10 to 21, 28 to 38, and 42 to 52, a loop of residues 22 to 27 between the helices I and II, and a turn of residues 39 to 41 linking the helices II and III. Comparisons with the structure of the mutant Antennapedia homeodomain with Cys39 replaced by Ser, Antp (C39S), shows that the two proteins contain the same molecular fold for residues 8 to 53, whereas the more flexible fourth helix comprising residues 53 to 59 in the Antp (C39S) homeodomain has no counterpart in the ftz homeodomain. Considering that important intermolecular interactions in the DNA complexes with the Antp, engrailed and Mat alpha 2 homeodomains involve the fourth helix, it was rather unexpected that the stability of the complex of ftz with the BS2 operator site was found to be comparable to or even somewhat higher than that of the Antp complex with BS2. Another difference is that the Antp homeodomain is more stable with respect to thermal denaturation, with denaturation temperatures at pH 4.8 of 27 degrees C and 48 degrees C, respectively, for ftz and Antp.

Amino Acid Sequence↗

PubMed1992

Changes in dorsoventral but not rostrocaudal regionalization of the chick neural tube in the absence of cranial notochord, as revealed by expression of engrailed-2.

Notochord has been implicated in previous studies in both the dorsoventral and rostrocaudal patterning of the developing neural tube. This possibility has been further explored by analyzing the expression of Engrailed-2 in chick embryos developing with cranial notochord defects. Control embryos containing intact notochords expressed Engrailed-2 protein within the neural tube and in a subset of the neural crest and overlying surface ectoderm at the future mesencephalon and cranial metencephalon levels. Within the neural tube, expression was confined to cell nuclei in the roof plate and lateral walls; floor plate nuclei directly overlying the notochord typically failed to show expression. After surgical removal of Hensen's node, the source of notochord precursor cells, embryos were cultured through neurulation and assayed for expression of Engrailed-2 protein. All embryos that partially or completely lacked cranial notochord expressed Engrailed-2 in a pattern similar to that of control embryos containing intact notochords, except that when notochord and floor plate were absent, Engrailed-2 was also expressed in the most ventral part of the neural tube. These results indicate that 1) Engrailed-2 expression is suppressed in the most ventral neural tube owing to induction of the floor plate by the notochord, and 2) that the presence of an underlying notochord is not required for correct rostrocaudal expression, suggesting that multiple pathways act in the patterning of the rudiment of the central nervous system.

Animals↗

PubMed1991

Secondary structure of the homeo domain of yeast alpha 2 repressor determined by NMR spectroscopy.

The yeast alpha 2 protein is a regulator of cell type in Saccharomyces cerevisiae. It represses transcription of a set of target genes by binding to an operator located upstream of each of these genes. The alpha 2 protein shares weak sequence similarity with members of the homeo domain family; the homeo domain is a 60-amino-acid segment found in many eukaryotic transcriptional regulators. In this paper we address the question of whether alpha 2 is structurally related to prototypical members of the homeo domain family. We used solution 1H and 15N nuclear magnetic resonance [NMR] spectroscopy to determine the secondary structure of an 83-amino-acid residue fragment of alpha 2 that contains the homeo domain homology. We have obtained resonance assignments for the backbone protons and nitrogens of the entire 60-residue region of the putative homeo domain and for most of the remainder of the alpha 2 fragment. The secondary structure was determined by using NOE connectivities between backbone protons, 3JHN-H alpha coupling constants, and dynamical information from the hydrogen exchange kinetics of the backbone amides. Three helical segments exist in the alpha 2 fragment consisting of residues 11-23, 32-42, and 46-60 (corresponding to residues 138-150, 159-169, and 173-187 of the intact protein). The positions of these three helices correspond extremely well to those of the Drosophila Antennapedia (Antp) and engrailed (en) homeo domains, whose three-dimensional structures have recently been determined by NMR spectroscopy and X-ray crystallography, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed1996

Structure of the insect head as revealed by the EN protein pattern in developing embryos.

The structure of the insect head has long been a topic of enjoyable yet endless debate among entomologists. More recently geneticists and molecular biologists trying to better understand the structure of the head of the Dipteran Drosophila melanogaster have joined the discourse extrapolating from what they have learned about Drosophila to insects in general. Here we present the results of an investigation into the structure of the insect head as revealed by the distribution of engrailed related protein (Engrailed) in the insect orders Diptera, Siphonaptera, Orthoptera and Hemiptera. The results of this comparative embryology in conjunction with genetic experiments on Drosophila melanogaster lead us to conclude: (1) The insect head is composed of six Engrailed accumulating segments, four postoral and two preoral. The potential seventh and eighth segments (clypeus or labrum) do not accumulate Engrailed. (2) The structure known as the dorsal ridge is not specific to the Diptera but is homologous to structures found in other insect orders. (3) A part of this structure is a single segment-like entity composed of labial and maxillary segment derivatives which produce the most anterior cuticle capable of taking a dorsal fate. The segments anterior to the maxillary segment produce only ventral structures. (4) As in Drosophila, the process of segmentation of the insect head is fundamentally different from the process of segmentation in the trunk. (5) The pattern of Engrailed accumulation and its presumed role in the specification and development of head segments appears to be highly conserved while its role in other pattern formation events and tissue-specific expression is variable. An overview of the pattern of Engrailed accumulation in developing insect embryos provides a basis for discussion of the generality of the parasegment and the evolution of Engrailed patterns.

Animals↗

PubMed1999

hedgehog and engrailed: pattern formation and polarity in the Drosophila abdomen.

Like the Drosophila embryo, the abdomen of the adult consists of alternating anterior (A) and posterior (P) compartments. However the wing is made by only part of one A and part of one P compartment. The abdomen therefore offers an opportunity to compare two compartment borders (A/P is within the segment and P/A intervenes between two segments), and ask if they act differently in pattern formation. In the embryo, abdomen and wing P compartment cells express the selector gene engrailed and secrete Hedgehog protein whilst A compartment cells need the patched and smoothened genes in order to respond to Hedgehog. We made clones of cells with altered activities of the engrailed, patched and smoothened genes. Our results confirm (1) that the state of engrailed, whether 'off' or 'on', determines whether a cell is of A or P type and (2) that Hedgehog signalling, coming from the adjacent P compartments across both A/P and P/A boundaries, organises the pattern of all the A cells. We have uncovered four new aspects of compartments and engrailed in the abdomen. First, we show that engrailed acts in the A compartment: Hedgehog leaves the P cells and crosses the A/P boundary where it induces engrailed in a narrow band of A cells. engrailed causes these cells to form a special type of cuticle. No similar effect occurs when Hedgehog crosses the P/A border. Second, we look at the polarity changes induced by the clones, and build a working hypothesis that polarity is organised, in both compartments, by molecule(s) emanating from the A/P but not the P/A boundaries. Third, we show that both the A and P compartments are each divided into anterior and posterior subdomains. This additional stratification makes the A/P and the P/A boundaries fundamentally distinct from each other. Finally, we find that when engrailed is removed from P cells (of, say, segment A5) they transform not into A cells of the same segment, but into A cells of the same parasegment (segment A6).

Abdomen↗

PubMed2002

GATA6 regulates differentiation of distal lung epithelium.

GATA6 is a member of the GATA family of zinc-finger transcriptional regulators and is the only known GATA factor expressed in the distal epithelium of the lung during development. To define the role that GATA6 plays during lung epithelial cell development, we expressed a GATA6-Engrailed dominant-negative fusion protein in the distal lung epithelium of transgenic mice. Transgenic embryos lacked detectable alveolar epithelial type 1 cells in the distal airway epithelium. These embryos also exhibited increased Foxp2 gene expression, suggesting a disruption in late alveolar epithelial differentiation. Alveolar epithelial type 2 cells, which are progenitors of alveolar epithelial type 1 cells, were correctly specified as shown by normal thyroid transcription factor 1 and surfactant protein A gene expression. However, attenuated endogenous surfactant protein C expression indicated that alveolar epithelial type 2 cell differentiation was perturbed in transgenic embryos. The number of proximal airway tubules is also reduced in these embryos, suggesting a role for GATA6 in regulating distal-proximal airway development. Finally, a functional role for GATA factor function in alveolar epithelial type 1 cell gene regulation is supported by the ability of GATA6 to trans-activate the mouse aquaporin-5 promoter. Together, these data implicate GATA6 as an important regulator of distal epithelial cell differentiation and proximal airway development in the mouse.

Animals↗

PubMed1994

Unusual properties of regulatory DNA from the Drosophila engrailed gene: three "pairing-sensitive" sites within a 1.6-kb region.

We have previously shown that a 2-kb fragment of engrailed DNA can suppress expression of a linked marker gene, white, in the P element vector CaSpeR. This suppression is dependent on the presence of two copies of engrailed DNA-containing P elements (P[en]) in proximity in the Drosophila genome (either in cis or in trans). In this study, the 2-kb fragment was dissected and found to contain three fragments of DNA which could mediate white suppression [called "pairing-sensitive sites" (PS)]. A PS site was also identified in regulatory DNA from the Drosophila escargot gene. The eye colors of six different P[en] insertions in the escargot gene suggest an interaction between P[en]-encoded and genome-encoded PS sites. I hypothesize that white gene expression from P[en] is repressed by the formation of a protein complex which is initiated at the engrailed PS sites and also requires interactions with flanking genomic DNA. Genes were sought which influence the function of PS sites. Mutations in some Polycomb and trithorax group genes were found to affect the eye color from some P[en] insertion sites. However, different mutations affected expression from different P[en] insertion sites and no one mutation was found to affect expression from all P[en] insertion sites examined. These results suggest that white expression from P[en] is not directly regulated by members of the Polycomb and trithorax group genes, but in some cases can be influenced by them. I propose that engrailed PS sites normally act to promote interactions between distantly located engrailed regulatory sites and the engrailed promoter.

Animals↗

PubMed2005

Solution structure of the K50 class homeodomain PITX2 bound to DNA and implications for mutations that cause Rieger syndrome.

We have determined the solution structure of a complex containing the K50 class homeodomain Pituitary homeobox protein 2 (PITX2) bound to its consensus DNA site (TAATCC). Previous studies have suggested that residue 50 is an important determinant of differential DNA-binding specificity among homeodomains. Although structures of several homeodomain-DNA complexes have been determined, this is the first structure of a native K50 class homeodomain. The only K50 homeodomain structure determined previously is an X-ray crystal structure of an altered specificity mutant, Engrailed Q50K (EnQ50K). Analysis of the NMR structure of the PITX2 homeodomain indicates that the lysine at position 50 makes contacts with two guanines on the antisense strand of the DNA, adjacent to the TAAT core DNA sequence, consistent with the structure of EnQ50K. Our evidence suggests that this side chain may make fluctuating interactions with the DNA, which is complementary to the crystal data for EnQ50K. There are differences in the tertiary structure between the native K50 structure and that of EnQ50K, which may explain differences in affinity and specificity between these proteins. Mutations in the human PITX2 gene are responsible for Rieger syndrome, an autosomal dominant disorder. Analysis of the residues mutated in Rieger syndrome indicates that many of these residues are involved in DNA binding, while others are involved in formation of the hydrophobic core of the protein. Overall, the role of K50 in homeodomain recognition is further clarified, and the results indicate that native K50 homeodomains may exhibit differences from altered specificity mutants.

Abnormalities, Multiple↗

PubMed1998

Comparative gene mapping: cytogenetic localization of PROC, EN1, ALPI, TNP1, and IL1B in cattle and sheep reveals a conserved rearrangement relative to the human genome.

The cytogenetic locations of the genes for protein C (PROC), transition protein 1 (TNP1), intestinal alkaline phosphatase (ALPI), engrailed (EN1), and human protointerleukin beta (IL1B) have been compared between cattle (Bos taurus, BTA) and sheep (Ovis aries, OAR). Bovine YAC and cosmid clones were used as FISH probes to determine the order (centromere to telomere) of four of these genes on OAR 2q, as well as the location of IL1B on OAR 3p. In cattle, IL1B and EN1 were assigned to BTA 11 and BTA 2, respectively. Alignment of the ovine, bovine, and human physical maps based on these data shows that segments of conserved synteny and chromosomal rearrangements detected between cattle and human are also found in sheep, where the order in cattle is conserved.

Adaptor Proteins, Signal Transducing↗

PubMed1991

The doublesex locus of Drosophila melanogaster and its flanking regions: a cytogenetic analysis.

The region of the third chromosome (84D-F) of Drosophila melanogaster that contains the doublesex (dsx) locus has been cytogenetically analyzed. Twenty nine newly induced, and 42 preexisting rearrangements broken in dsx and the regions flanking dsx have been cytologically and genetically characterized. These studies established that the dsx locus is in salivary chromosome band 84E1-2. In addition, these observations provide strong evidence that the dsx locus functions only to regulate sexual differentiation and does not encode a vital function. To obtain new alleles at the dsx locus and to begin to analyze the genes flanking dsx, 59 lethal and visible mutations in a region encompassing dsx were induced. These mutations together with preexisting mutations in the region were deficiency mapped and placed into complementation groups. Among the mutations we isolated, four new mutations affecting sexual differentiation were identified. All proved to be alleles of dsx, suggesting that dsx is the only gene in this region involved in regulating sexual differentiation. All but one of the new dsx alleles have equivalent effects in males and females. The exception, dsxEFH55, strongly affects female sexual differentiation, but only weakly affects male sexual differentiation. The interactions of dsxEFH55 with mutations in other genes affecting sexual differentiation are described. These results are discussed in terms of the recent molecular findings that the dsx locus encodes sex-specific proteins that share in common their amino termini but have different carboxyl termini. The 72 mutations in this region that do not affect sexual differentiation identify 25 complementation groups. A translocation, T(2;3)Es that is associated with a lethal allele in one of these complementation groups is also broken at the engrailed (en) locus on the second chromosome and has a dominant phenotype that may be due to the expression of en in the anterior portion of the abdominal tergites where en is not normally expressed. The essential genes found in the 84D-F region are not evenly distributed throughout this region; most strikingly the 84D1-11 region appears to be devoid of essential genes. It is suggested that the lack of essential genes in this region is due to the region (1) containing genes with nonessential functions and (2) being duplicated, possibly both internally and elsewhere in the genome.

Alleles↗

PubMed2003

Transcriptional regulation of BMP-2 activated genes in osteoblasts using gene expression microarray analysis: role of Dlx2 and Dlx5 transcription factors.

This presentation will focus on using microarray data on a clonal osteoblast cell model to analyze the early BMP-2 responsive genes, as well as some of the later genes regulated by BMP2 during different phases of mineralization. We will focus on the early phases of gene expression that occur after BMP2 signaling from 30 min up to 1 day. The hypothesis is that understanding how these early genes are regulated during the initial multilayering and growth phase of osteoblasts will lead to models of how BMP activity stimulates cell growth, cell migration, multilayering, matrix deposition and remodeling phase that allows subsequent mineralization. The Dlx2 and Dlx5 homeobox genes have been shown to be critical for bone formation both in vitro and in vivo. Both Dlx 2 and Dlx5 are activated within 15-30 minutes after BMP2 addition to the mouse 2T3 osteoblast model and primary fetal rat calvarial osteoblasts. The Dlx2 and Dlx5 genes stay elevated in the presence of BMP2 for up to 5 days, a time when overt mineralization is just beginning. To understand the genomic network that Dlx5 and Dlx2 regulate at the transcription level, we have taken an approach where we use a specific transcription repressor protein, Engrailed, ligated to the Dlx5 homeodomain. The idea is that this Eng-Dlx5 protein will interact with Dlx5 and possibly Dlx2 and related Dlx- regulated genes in vivo and down-regulate their transcriptional initiation. Using a microarray approach with over 5,000 known genes we can identify the genes that are directly and indirectly regulated by Dlx5 and Dlx2. This will allow us to build an initial genomic network of Dlx- regulated genes at the transcriptional level. We will present our model and preliminary efforts at understanding the genomic network regulated by this important BMP2-regulated transcription factor class in osteoblast biology.

Animals↗

PubMed2003

Midbrain dopaminergic neurons: determination of their developmental fate by transcription factors.

Midbrain dopaminergic neurons are the main source of dopamine in the mammalian central nervous system and are associated with one of the most prominent human neurological disorders, Parkinson's disease. During development, they are induced in the ventral midbrain by an interaction between two diffusible factors, SHH and FGF8. The local identity of this part of the midbrain is probably determined by the combinatorial expression of three transcription factors, Otx2, Pax2, and Pax5. After the last cell division, the neurons start to express transcription factors that control further differentiation and the manifestation of cellular properties characteristic for adult dopaminergic neurons of the substantia nigra compacta and the ventral tegmentum. The first to appear is the LIM-homeodomain transcription factor, Lmx1b. It is essential for the survival of these neurons, and it regulates the expression of another transcription factor, Pitx3, an activator of tyrosine hydroxylase. Lmx1b is followed by the orphan steroid receptor Nurr1. It is essential for the expression of the dopaminergic phenotype. Several genes involved in dopamine synthesis, transport, release, and reuptake are regulated by Nurr1. This requirement is specific to the midbrain dopaminergic neurons, since other populations of the same neurotransmitter phenotype develop normally in absence of the gene. A day after Nurr1, two homeodomain transcription factors, engrailed-1 and -2, are expressed. In animals deficient in the two genes, the midbrain dopaminergic neurons are generated, but then fail to differentiate and disappear very rapidly. Interestingly, alpha-synuclein, a gene recently linked to familial forms of Parkinson's disease, is regulated by engrailed-1 and -2.

Animals↗

PubMed1998

Hedgehog and wingless induce metameric pattern in the Drosophila visceral mesoderm.

The Drosophila visceral mesoderm (VM) is a favorite system for studying the regulation of target genes by Hox proteins. The VM is formed by cells from only the anterior subdivision of each mesodermal parasegment (PS). We show here that the VM itself acquires modular anterior-posterior subdivisions similar to those found in the ectoderm. As VM progenitors merge to form a continuous band running anterior to posterior along the embryo, expression of connectin (con) in 11 metameric patches within the VM reveals VM subdivisions analagous to ectodermal compartments. The VM subdivisions form in response to ectodermal production of secreted signals encoded by the segment polarity genes hedgehog (hh) and wingless (wg) and are independent of Hox gene activity. A cascade of induction from ectoderm to mesoderm to endoderm thus subdivides the gut tissues along the A-P axis. Induction of VM subdivisions may converge with Hox-mediated information to refine spatial patterning in the VM. Con patches align with ectodermal engrailed stripes, so the VM subdivisions correspond to PS 2-12 boundaries in the VM. The PS boundaries demarcated by Con in the VM can be used to map expression domains of Hox genes and their targets with high resolution. The resultant map suggests a model for the origins of VM-specific Hox expression in which Hox domains clonally inherited from blastoderm ancestors are modified by diffusible signals acting on VM-specific enhancers.

Animals↗