Biomedical subjects

J Modolell

Publications and source records attributed to J Modolell.

At least 19 recordsLinked to original sources

PubMed2001

From first base: the sequence of the tip of the X chromosome of Drosophila melanogaster, a comparison of two sequencing strategies.

We present the sequence of a contiguous 2.63 Mb of DNA extending from the tip of the X chromosome of Drosophila melanogaster. Within this sequence, we predict 277 protein coding genes, of which 94 had been sequenced already in the course of studying the biology of their gene products, and examples of 12 different transposable elements. We show that an interval between bands 3A2 and 3C2, believed in the 1970s to show a correlation between the number of bands on the polytene chromosomes and the 20 genes identified by conventional genetics, is predicted to contain 45 genes from its DNA sequence. We have determined the insertion sites of P-elements from 111 mutant lines, about half of which are in a position likely to affect the expression of novel predicted genes, thus representing a resource for subsequent functional genomic analysis. We compare the European Drosophila Genome Project sequence with the corresponding part of the independently assembled and annotated Joint Sequence determined through "shotgun" sequencing. Discounting differences in the distribution of known transposable elements between the strains sequenced in the two projects, we detected three major sequence differences, two of which are probably explained by errors in assembly; the origin of the third major difference is unclear. In addition there are eight sequence gaps within the Joint Sequence. At least six of these eight gaps are likely to be sites of transposable elements; the other two are complex. Of the 275 genes in common to both projects, 60% are identical within 1% of their predicted amino-acid sequence and 31% show minor differences such as in choice of translation initiation or termination codons; the remaining 9% show major differences in interpretation.

Animals↗

PubMed2001

The Iroquois family of genes: from body building to neural patterning.

The Iroquois (Iro) family of genes are found in nematodes, insects and vertebrates. They usually occur in one or two genomic clusters of three genes each and encode transcriptional controllers that possess a characteristic homeodomain. The Iro genes function early in development to specify the identity of diverse territories of the body, such as the dorsal head and dorsal mesothorax of Drosophila and the neural plate of Xenopus. In some aspects they act in the same way as classical selector genes, but they display specific properties that place them into a category of their own. Later in development in both Drosophila and vertebrates, the Iro genes function again to subdivide those territories into smaller domains.

Animals↗

PubMed2001

The EGF receptor and N signalling pathways act antagonistically in Drosophila mesothorax bristle patterning.

An early step in the development of the large mesothoracic bristles (macrochaetae) of Drosophila is the expression of the proneural genes of the achaete-scute complex (AS-C) in small groups of cells (proneural clusters) of the wing imaginal disc. This is followed by a much increased accumulation of AS-C proneural proteins in the cell that will give rise to the sensory organ, the SMC (sensory organ mother cell). This accumulation is driven by cis-regulatory sequences, SMC-specific enhancers, that permit self-stimulation of the achaete, scute and asense proneural genes. Negative interactions among the cells of the cluster, triggered by the proneural proteins and mediated by the Notch receptor (lateral inhibition), block this accumulation in most cluster cells, thereby limiting the number of SMCs. Here we show that the proneural proteins trigger, in addition, positive interactions among cells of the cluster that are mediated by the Epidermal growth factor receptor (EGFR) and the Ras/Raf pathway. These interactions, which we denominate 'lateral co-operation', are essential for macrochaetae SMC emergence. Activation of the EGFR/Ras pathway appears to promote proneural gene self-stimulation mediated by the SMC-specific enhancers. Excess EGFR signalling can overrule lateral inhibition and allow adjacent cells to become SMCs and sensory organs. Thus, the EGFR and Notch pathways act antagonistically in notum macrochaetae determination.

Animals↗

PubMed2001

The Wnt-activated Xiro1 gene encodes a repressor that is essential for neural development and downregulates Bmp4.

In the early Xenopus embryo, the Xiro homeodomain proteins of the Iroquois (Iro) family control the expression of proneural genes and the size of the neural plate. We report that Xiro1 functions as a repressor that is strictly required for neural differentiation, even when the BMP4 pathway is impaired. We also show that Xiro1 and Bmp4 repress each other. Consistently, Xiro1 and Bmp4 have complementary patterns of expression during gastrulation. The expression of Xiro1 requires Wnt signaling. Thus, Xiro1 is probably a mediator of the known downregulation of Bmp4 by Wnt signaling.

Animals↗

PubMed2000

From sequence to chromosome: the tip of the X chromosome of D. melanogaster.

One of the rewards of having a Drosophila melanogaster whole-genome sequence will be the potential to understand the molecular bases for structural features of chromosomes that have been a long-standing puzzle. Analysis of 2.6 megabases of sequence from the tip of the X chromosome of Drosophila identifies 273 genes. Cloned DNAs from the characteristic bulbous structure at the tip of the X chromosome in the region of the broad complex display an unusual pattern of in situ hybridization. Sequence analysis revealed that this region comprises 154 kilobases of DNA flanked by 1.2-kilobases of inverted repeats, each composed of a 350-base pair satellite related element. Thus, some aspects of chromosome structure appear to be revealed directly within the DNA sequence itself.

Animals↗

PubMed2000

The Iroquois homeobox genes function as dorsal selectors in the Drosophila head.

The Iroquois complex (Iro-C) genes are expressed in the dorsal compartment of the Drosophila eye/antenna imaginal disc. Previous work has shown that the Iro-C homeoproteins are essential for establishing a dorsoventral pattern organizing center necessary for eye development. Here we show that, in addition, the Iro-C products are required for the specification of dorsal head structures. In mosaic animals, the removal of the Iro-C transforms the dorsal head capsule into ventral structures, namely, ptilinum, prefrons and suborbital bristles. Moreover, the Iro-C(-) cells can give rise to an ectopic antenna and maxillary palpus, the main derivatives of the antenna part of the imaginal disc. These transformations are cell-autonomous, which indicates that the descendants of a dorsal Iro-C(-) cell can give rise to essentially all the ventral derivatives of the eye/antenna disc. These results support a role of the Iro-C as a dorsal selector in the eye and head capsule. Moreover, they reinforce the idea that developmental cues inherited from the distinct embryonic segments from which the eye/antenna disc originates play a minimal role in the patterning of this disc.

Animals↗

PubMed1999

The Iroquois homeodomain proteins are required to specify body wall identity in Drosophila.

The Iroquois complex (Iro-C) homeodomain proteins allow cells at the proximal part of the Drosophila imaginal wing disc to form mesothoracic body wall (notum). Cells lacking these proteins form wing hinge structures instead (tegula and axillary sclerites). Moreover, the mutant cells impose on neighboring wild-type cells more distal developmental fates, like lateral notum or wing hinge. These findings support a tergal phylogenetic origin for the most proximal part of the wing and provide evidence for a novel pattern organizing center at the border between the apposed notum (Iro-C-expressing) and hinge (Iro-C-nonexpressing) cells. This border is not a cell lineage restriction boundary.

Animals↗

PubMed1999

Xenopus brain factor-2 controls mesoderm, forebrain and neural crest development.

The forkhead type Brain Factor 2 from mouse and chicken help pattern the forebrain, optic vesicle and kidney. We have isolated a Xenopus homolog (Xbf2) and found that during gastrulation it is expressed in the dorsolateral mesoderm, where it helps specify this territory by downregulating BMP-4 and its downstream genes. Indeed, Xbf2 overexpression caused partial axis duplication. Interference with BMP-4 signaling also occurs in isolated animal caps, since Xbf2 induces neural tissue. Within the neurula forebrain, Xbf2 and the related Xbf1 gene are expressed in the contiguous diencephalic and telencephalic territories, respectively, and each gene represses the other. Finally, Xbf2 seems to participate in the control of neural crest migration. Our data suggest that XBF2 interferes with BMP-4 signaling, both in mesoderm and ectoderm.

Amino Acid Sequence↗

PubMed1999

Different contributions of pannier and wingless to the patterning of the dorsal mesothorax of Drosophila.

In Drosophila, the GATA family transcription factor Pannier and the Wnt secreted protein Wingless are known to be important for the patterning of the notum, a part of the dorsal mesothorax of the fly. Thus, both proteins are necessary for the development of the dorsocentral mechanosensory bristles, although their roles in this process have not been clarified. Here, we show that Pannier directly activates the proneural genes achaete and scute by binding to the enhancer responsible for the expression of these genes in the dorsocentral proneural cluster. Moreover, the boundary of the expression domain of Pannier appears to delimit the proneural cluster laterally, while antagonism of Pannier function by the Zn-finger protein U-shaped sets its limit dorsally. So, Pannier and U-shaped provide positional information for the patterning of the dorsocentral cluster. In contrast and contrary to previous suggestions, Wingless does not play a similar role, since the levels and vectorial orientation of its concentration gradient in the dorsocentral area can be greatly modified without affecting the position of the dorsocentral cluster. Thus, Wingless has only a permissive role on dorsocentral achaete-scute expression. We also provide evidence indicating that Pannier and U-shaped are main effectors of the regulation of wingless expression in the presumptive notum.

Animals↗

PubMed1998

Proneural gene self-stimulation in neural precursors: an essential mechanism for sense organ development that is regulated by Notch signaling.

To learn about the acquisition of neural fate by ectodermal cells, we have analyzed a very early sign of neural commitment in Drosophila, namely the specific accumulation of achaete-scute complex (AS-C) proneural proteins in the cell that becomes a sensory organ mother cell (SMC). We have characterized an AS-C enhancer that directs expression specifically in SMCs. This enhancer promotes Scute protein accumulation in these cells, an event essential for sensory organ development in the absence of other AS-C genes. Interspecific sequence comparisons and site-directed mutagenesis show the presence of several conserved motifs necessary for enhancer action, some of them binding sites for proneural proteins. These and other data indicate that the enhancer mediates scute self-stimulation, although only in the presence of additional activating factors, which most likely interact with conserved motifs reminiscent of NF-kappaB-binding sites. Cells neighboring the SMC do not acquire the neural fate because the Notch signaling pathway effectors, the Enhancer of split bHLH proteins, block this proneural gene self-stimulatory loop, possibly by antagonizing the action on the enhancer of the NF-kappaB-like factors or the proneural proteins. These data suggest a mechanism for SMC committment.

Animals↗

PubMed1998

Xiro, a Xenopus homolog of the Drosophila Iroquois complex genes, controls development at the neural plate.

The Drosophila homeoproteins Ara and Caup are members of a combination of factors (prepattern) that control the highly localized expression of the proneural genes achaete and scute. We have identified two Xenopus homologs of ara and caup, Xiro1 and Xiro2. Similarly to their Drosophila counterparts, they control the expression of proneural genes and, probably as a consequence, the size of the neural plate. Moreover, Xiro1 and Xiro2 are themselves controlled by noggin and retinoic acid and, similarly to ara and caup, they are overexpressed by expression in Xenopus embryos of the Drosophila cubitus interruptus gene. These and other findings suggest the conservation of at least part of the genetic cascade that regulates proneural genes, and the existence in vertebrates of a prepattern of factors important to control the differentiation of the neural plate.

Amino Acid Sequence↗

PubMed1998

The achaete-scute complex as an integrating device.

A classical model to study pattern formation is provided by the epidermal sensory organs (bristles and other sensilla) that cover the body of Drosophila. Many of these sensory organs (SOs) arise in very constant positions. How are these positions specified? To a large extent, they are defined by the highly resolved sites of expression of the proneural genes of the achaete-scute complex (AS-C). These genes, which confer to cells the capacity to become SO precursors, attain their resolved patterns of expression by means of many position-specific enhancers located within the non-transcribed AS-C DNA. Each enhancer drives expression at one or very few sites. Evidence is growing that the enhancers interact with combinations of activators and repressors (prepattern) distributed in partially overlapping domains which are larger than the AS-C expressing sites. AS-C transcription is activated only at sites with appropriate combinations of factors. Thus, the AS-C integrates the positional information embodied in the relatively broad distributions of prepattern factors and creates a sharper and topographically more precise pattern.

Animals↗

PubMed1997

One-hundred and five new potential Drosophila melanogaster genes revealed through STS analysis.

Complementation analysis had suggested that the Drosophila melanogaster genome contains approximately 5000 genes, but it is now generally accepted that the actual number is several times as high. We report here an analysis of 1788 anonymous sequence tagged sites (STSs) from the European Drosophila Genome Project (EDGP), totalling 463 kb. The data reveal a substantial number of previously undescribed potential genes, amounting to 6.1% of the number of Drosophila genes already in the sequence databases.

Amino Acid Sequence↗

PubMed1997

Identification of the vertebrate Iroquois homeobox gene family with overlapping expression during early development of the nervous system.

In Drosophila the decision processes between the neural and epidermal fate for equipotent ectodermal cells depend on the activity of proneural genes. Members of the Drosophila Iroquois-Complex (Iro-C) positively regulate the activity of certain proneural AS-C genes during the formation of external sensory organs. We have identified and characterized three mouse Iroquois-related genes: Irx1, -2 and -3, which have a homeodomain very similar to that of the Drosophila Iro-C genes. The sequence similarity implies that these three genes represent a separate homeobox family. All three genes are expressed with distinct spatio/temporal patterns during early mouse embryogenesis. These patterns implicate them in a number of embryonic developmental processes: the A/P and D/V patterning of specific regions of the central nervous system (CNS), and regionalization of the otic vesicle, branchial epithelium and limbs.

Amino Acid Sequence↗

PubMed1997

P-element insertion alleles of essential genes on the third chromosome of Drosophila melanogaster: correlation of physical and cytogenetic maps in chromosomal region 86E-87F.

We have established a collection of 2460 lethal or semi-lethal mutant lines using a procedure thought to insert single P elements into vital genes on the third chromosome of Drosophila melanogaster. More than 1200 randomly selected lines were examined by in situ hybridization and 90% found to contain single insertions at sites that mark 89% of all lettered subdivisions of the Bridges' map. A set of chromosomal deficiencies that collectively uncover approximately 25% of the euchromatin of chromosome 3 reveal lethal mutations in 468 lines corresponding to 145 complementation groups. We undertook a detailed analysis of the cytogenetic interval 86E-87F and identified 87 P-element-induced mutations falling into 38 complementation groups, 16 of which correspond to previously known genes. Twenty-one of these 38 complementation groups have at least one allele that has a P-element insertion at a position consistent with the cytogenetics of the locus. We have rescued P elements and flanking chromosomal sequences from the 86E-87F region in 35 lines with either lethal or genetically silent P insertions, and used these as probes to identify cosmids and P1 clones from the Drosophila genome projects. This has tied together the physical and genetic maps and has linked 44 previously identified cosmid contigs into seven "super-contigs" that span the interval. STS data for sequences flanking one side of the P-element insertions in 49 lines has identified insertions in the alphagamma element at 87C, two known transposable elements, and the open reading frames of seven putative single copy genes. These correspond to five known genes in this interval, and two genes identified by the homology of their predicted products to known proteins from other organisms.

Alleles↗

PubMed1997

Patterning of the adult peripheral nervous system of Drosophila.

The peripheral nervous system (PNS) of the adult Drosophila melanogaster comprises over one thousand sensory organs (bristles and other types of sensilla) displayed in stereotyped positions of the epidermis. This two-dimensional pattern of sensory organs is generated by the emergence of the sensillum mother cells at specific positions of the imaginal discs, the precursors of the adult epidermis. These positions are largely specified by the interplay of three sets of genes: the proneural genes, their antagonists, and the neurogenic genes. The proneural genes confer upon cells the ability to become neural precursors. Among them, achaete and scute, two genes that encode transcriptional activators of the basic region-helix-loop-helix (bHLH) family, are most important for generating the adult PNS. Their expression is restricted to groups of cells, the proneural clusters, which appear at specific positions of the imaginal discs. Sensory organ precursor cells are born within these clusters. The known proneural antagonists either titrate these proteins by forming inactive complexes (extramacrochaetae) or repress achaete/scute expression at specific sites (i.e., hairy). In both cases, they refine sensory organ positioning by reducing the number of cells competent to become sensory organs. The neurogenic genes mediate cell-cell interactions that prevent most competent cells of a proneural cluster from becoming sensory organ mother cells. Depending on the size and shape of the proneural clusters and on their overlaps with regions of maxima or minima of expression of antagonists, sensory organs are generated either as single elements at unique positions, or as linear arrays containing many elements, or as characteristically shaped, two-dimensional arrangements covering specific regions of the fly's body.

Animals↗

PubMed1996

araucan and caupolican provide a link between compartment subdivisions and patterning of sensory organs and veins in the Drosophila wing.

The homeo box prepattern genes araucan (ara) and caupolican (caup) are coexpressed near the anterior-posterior (AP) compartment border of the developing Drosophila wing in two symmetrical patches located one at each side of the dorsoventral (DV) compartment border. ara-caup expression at these patches is necessary for the specification of the prospective vein L3 and associated sensory organs through the transcriptional activation, in smaller overlapping domains, of rhomboid/veinlet and the proneural genes achaete and scute. We show that ara-caup expression at those patches is mediated by the Hedgehog signal through its induction of high levels of Cubitus interruptus (Ci) protein in anterior cells near to the AP compartment border. The high levels of Ci activate decapentaplegic (dpp) expression, and, together, Ci and Dpp positively control ara-caup. The posterior border of the patches is apparently defined by repression by engrailed. Wingless accumulation at the DV border sets, also by repression, the gap between the two patches. Thus, ara and caup integrate the inputs of genes effecting the primary subdivisions of the wing disc into compartments to define two smaller territories. These in turn help create the even smaller domains of rhomboid/veinlet and achaete-scute expression.

Animals↗

PubMed1996

Araucan and caupolican, two members of the novel iroquois complex, encode homeoproteins that control proneural and vein-forming genes.

In Drosophila imaginal wing discs, the achaete-scute (ac-sc) proneural genes and rhomboid (veinlet) are expressed in highly resolved patterns that prefigure the positions of sensory organs and wing veins, respectively. It is thought that these patterns are generated by a combination of factors (a prepattern) regulating these genes. We provide evidence for the existence of this prepattern by identifying two of its factors, Araucan and Caupolican. They are members of a novel family of homeoproteins, with homologs in vertebrates. Araucan and Caupolican, present in domains of the imaginal discs larger than those expressing ac-sc and rhomboid, are necessary for expression of these genes in the overlapping domains. Araucan and Caupolican appear to be positive, direct regulators of ac-sc.

Alleles↗