pinecone/core-2020-05-10-deduplication huggingface dataset:
Dorsal–Ventral Patterning Defects in the Eye of BF-1-Deficient Mice Associated with a Restricted Loss of shh Expression

AbstractBrain factor 1 (BF-1) is a winged-helix transcription factor with restricted expression in the anterior optic vesicle and in the telencephalic neuroepithelium of the neural tube. We have previously found that targeted disruption of the BF-1 gene results in hypoplasia of the cerebral hemispheres, which is more severe in structures derived from the ventral telencephalon. Here we show that the loss of BF-1 leads to multiple developmental anomalies of the eyes. The most ventral structure arising from the optic vesicle, the optic stalk, is missing and is replaced by an expanded retina. Ventral closure of the optic cup and choroid fissure does not occur. These dorsal–ventral patterning defects are not limited to the BF-1-expressing (anterior) cells, but also involve the cells of the posterior optic vesicle. Sonic hedgehog (shh) expression within the ventral telencephalic neuroepithelium is specifically lost in the BF-1(−/−) mutant. Taken together, these findings suggest that shh produced at this site plays a role in patterning the developing eye. This localized deficit in shh expression may also contribute to the prominence of the ventral defects in the telencephalon of the BF-1(−/−) mutant
PDGFB Regulates the Development of the Labyrinthine Layer of the Mouse Fetal Placenta

AbstractPDGFB is a growth factor which is vital for the completion of normal prenatal development. In this study, we report the phenotypic analysis of placentas from mouse conceptuses that lack a functional PDGFB or PDGFRβ gene. Placentas of both types of mutant exhibit changes in the labyrinthine layer, including dilated embryonic blood vessels and reduced numbers of both pericytes and trophoblasts. These changes are seen from embryonic day (E) 13.5, which coincides with the upregulation of PDGFB mRNA levels in normal placentas. By E17, modifications in shape, size, and number of the fetal blood vessels in the mutant placentas cause an abnormal ratio of the surface areas between the fetal and the maternal blood vessels in the labyrinthine layer. Our data suggest that PDGFB acts locally to contribute to the development of the labyrinthine layer of the fetal placenta and the formation of a proper nutrient–waste exchange system during fetal development. We point out that the roles of PDGFB/Rβ signaling in the placenta may be analogous to those in the developing kidney, by controlling pericytes in the labyrinthine layer and mesangial cells in the kidney
The Transcription Factor MEF2C-Null Mouse Exhibits Complex Vascular Malformations and Reduced Cardiac Expression of Angiopoietin 1 and VEGF

AbstractThe MEF2 family of transcription factors has been implicated in transcriptional regulation in a number of different cell types. Targeted deletion of the MEF2C gene, in particular, revealed its importance for early cardiogenesis (Q. Lin et al., 1997, Science 276, 1404–1407). We report here that this deletion also resulted in vascular anomalies characterized by extreme variability in lumen size and defects in remodeling. While primary vascular networks formed in the yolk sac of the mutants, they failed to remodel into more complex vascular structures. Likewise, although the primordia of the dorsal aortae formed normally, anomalies were observed in these vessels later in development. Dorsal and anterior to the heart, the aortae exhibited abnormally small lumens, as did the anterior cardinal veins and intersegmental arteries. In contrast, the dorsal aortae and intersegmental arteries caudal to the heart were grossly enlarged. Cranial vessels were also enlarged and less branched than normal. Endocardiogenesis in the mutant was abnormal with the endothelial cells exhibiting a number of aberrant phenotypes. These endocardial defects were accompanied by a notable reduction in angiopoietin 1 and VEGF mRNA production by the myocardium, indicating that MEF2C is required for myocardial expression of these important endothelial-directed cytokines and thus for correct endocardial morphogenesis
Morphological Domains of Lewis-X/FORSE-1 Immunolabeling in the Embryonic Neural Tube Are Due to Developmental Regulation of Cell Surface Carbohydrate Expression

AbstractThe Lewis-X (LeX) carbohydrate epitope, recognized by the FORSE-1 monoclonal antibody (mAb), shares expression boundaries with neural regulatory genes and may be involved in patterning the neural tube by creating domains of differential cell adhesion. The present experiments focus on the question of what determines the expression pattern of LeX in embryonic rat brain. Comparisons of FORSE-1-positive glycolipid and protein antigens in embryonic, early postnatal, and adult tissues show that the LeX epitope is carried primarily by glycolipids during embryonic development and by a proteoglycan and glycoproteins in postnatal and adult tissue. Immunohistochemistry using FORSE-1 and an antibody to the proteoglycan phosphacan, which carries LeX, shows that the distribution of LeX is more restricted than phosphacan. These observations suggest that the precise spatial regulation of FORSE-1 binding in the embryonic forebrain is due to the expression pattern of the LeX carbohydrate on glycolipids, rather than to the transcriptional regulation of a carrier protein
A Common Mechanism for Antenna-to-Leg Transformation in Drosophila: Suppression of homothorax Transcription by Four HOM-C Genes

AbstractThe Drosophila HOM-C genes encode transcription factors containing the DNA-binding homeodomain. Mutations in the HOM-C genes can cause specific homeotic transformation, suggesting that the HOM-C genes determine segmental identities by acting on different target genes. However, misexpression of several HOM-C genes in the antenna disc causes similar antenna-to-leg transformations. Here we show that the Scr, Antp, Ubx, and abd-A HOM-C genes all exert their effects through a common mechanism: suppressing the transcription of the homothorax (hth) homeobox gene and thereby preventing the nuclear localization of the Extradenticle homeodomain protein. We also show that ectopic hth expression can cause duplication of the proximodistal axis of the antenna, suggesting that it is involved in proximodistal development of the antenna
Neurestin: Putative Transmembrane Molecule Implicated in Neuronal Development

AbstractWe have cloned a novel cDNA encoding a putative transmembrane protein, neurestin, from the rat olfactory bulb. Neurestin was identified based on a sequence similar to that of the second extracellular loops of odorant receptors in the cysteine-rich CC box located immediately after EGF-like motifs. Neurestin shows homology to a neuregulin gene product, human γ-heregulin, a Drosophila receptor-type pair-rule gene product, Odd Oz (Odz) / Tenm, and Tena, suggesting a possible function in synapse formation and morphogenesis. Recently, a mouse neurestin homolog has independently been cloned as DOC4 from the NIH-3T3 cell line. Northern blot analysis showed that neurestin is highly expressed in the brain and also in other tissues at much lower levels. In situ hybridization studies showed that neurestin is expressed in many types of neurons, including pyramidal cells in the cerebral cortex and tufted cells in the olfactory bulb during development. In adults, neurestin is mainly expressed in olfactory and hippocampal granule cells, which are known to be generated throughout adulthood. Nonetheless, in adults the expression of neurestin was experimentally induced in external tufted cells during regeneration of olfactory sensory neurons. These results suggest a role for neurestin in neuronal development and regeneration in the central nervous system
Overexpression of ptc1 Inhibits Induction of Shh Target Genes and Prevents Normal Patterning in the Neural Tube

AbstractPatched (Ptc) is a human tumor suppressor protein and a candidate receptor for Hedgehog (Hh) proteins, which regulate growth and patterning in embryos. Ptc represses expression of Hh target genes such as Gli1 and ptc1 itself. Localized secretion of Hh appears to induce transcription of target genes in specific patterns by binding to Ptc and preventing it from functioning in recipient cells. People who are heterozygous for PTC1 exhibit a range of developmental defects, suggesting that some genes are inappropriately expressed when there is not enough Ptc protein. To test the idea that a balance between Hh and Ptc activities is essential for normal development, we overexpressed Ptc in the neural tube. We find that excess Ptc is sufficient to inhibit expression of Gli1 and ptc1, suggesting that Sonic hedgehog (Shh) cannot signal effectively. This leads to partial dorsalization of the neural tube and a wide spectrum of neural defects, ranging from embryonic lethality to hydrocephaly
Timp-1 Is Important for Epithelial Proliferation and Branching Morphogenesis during Mouse Mammary Development

AbstractThe dynamic process of mammary ductal morphogenesis depends on regulated epithelial proliferation and extracellular matrix (ECM) turnover. Epithelial cell–matrix contact closely dictates epithelial proliferation, differentiation, and survival. Despite the fact that tissue inhibitors of metalloproteinases (Timps) regulate ECM turnover, their function in mammary morphogenesis is unknown. We have delineated the spatiotemporal expression of all Timps (Timp-1 to Timp-4) during discrete phases of murine mammary development. Timp mRNAs were abundant in mammary tissue, each displaying differential expression patterns with predominant localization in luminal epithelial cells. Timp-1 mRNA was unique in that its expression was limited to the stage at which epithelial proliferation was high. To assess whether Timp-1 promotes or inhibits epithelial cell proliferation we manipulated mammary Timp-1 levels, genetically and biochemically. Down-regulation of epithelial-derived Timp-1 in transgenic mice, by mouse mammary tumor virus promoter-directed Timp-1 antisense RNA expression, led to augmented ductal expansion and increased number of ducts (P < 0.004). In these transgenics the integrity of basement membrane surrounding epithelial ducts, as visualized by laminin-specific immunostaining, was breached. In contrast to these mice, ductal expansion was markedly attenuated in the proximity of implanted recombinant Timp-1-releasing pellets (rTIMP-1), without an increase in basement membrane deposition around migrating terminal end buds. Epithelial proliferation and apoptosis were measured to determine the basis of altered ductal expansion. Luminal epithelial proliferation was increased by 55% (P < 0.02) in Timp-1-reduced transgenic mammary tissue and, conversely, decreased by 38% (P < 0.02) in terminal end buds by implanted rTIMP-1. Epithelial apoptosis was minimal and remained unaffected by Timp-1 manipulations. We conclude that Timps have an integral function in mammary morphogenesis and that Timp-1 regulates mammary epithelial proliferation in vivo, at least in part by maintaining basement membrane integrity
The Forkhead/Winged-Helix Gene, Mf1, Is Necessary for the Normal Development of the Cornea and Formation of the Anterior Chamber in the Mouse Eye

AbstractMf1, which encodes a winged-helix/forkhead transcription factor, is the murine homolog of human FKHL7, mutated in individuals with autosomal dominant inherited dysgenesis of the anterior segment of the eye (Axenfeld–Reiger anomaly). Mouse embryos homozygous for null mutations in Mf1 (Mf1lacZ and Mf1ch) show severely abnormal development of the anterior segment. The cornea fails to separate from the lens, resulting in the complete absence of an anterior chamber. There is no differentiation of the inner corneal endothelial layer, as judged by electron microscopy and by absence of labeling with monoclonal antibody to zonula occludens protein 1, a normal component of occluding junctions in wild-type endothelial cells. In addition, the mutant corneal stroma is disorganized and the epithelium thicker than normal. The Mf1 gene is normally expressed in the periocular mesenchyme at E11.5 but is downregulated as the corneal endothelium differentiates. In contrast, Mf1lacZ expression persists longer in mutant corneal mesenchyme, and abnormal expression is also seen in the mutant corneal epithelium. Based on classical studies with the chick embryonic eye, a model is proposed for the differentiation of the mammalian corneal endothelium from mesenchyme in response to putative signals from the lens. Possible roles for Mf1 in this process are discussed
Biphasic Dispersion of Clones Containing Purkinje Cells and Glia in the Developing Chick Cerebellum

AbstractThe cerebellum is a highly conserved structure which exhibits patterns of gene expression and axonal connections that are organized into parasagittal domains. These aspects of the mature cerebellum are presaged during embryonic development by the expression patterns of vertebrate homologs of Drosophila segmentation genes. We wished to determine whether the parasagittal domains of gene expression are compartments of lineage restriction. To this end, a clonal analysis of the chick cerebellum was conducted with a complex retroviral library. From embryonic day (E) 8 to E12, clones derived from the more medial portion of the cerebellar ventricular zone (VZ) were observed to spread preferentially in the mediolateral direction, crossing the boundaries of the parasagittal domains of gene expression. In late embryonic and posthatch periods, VZ clones were found to comprise Purkinje cells, glial cells, or both types of cells. At these later times, clonally related glial cells formed tight parasagittal clusters, while clonally related Purkinje cells were scattered extensively in the anteroposterior direction. We propose that a subset of the cerebellar VZ clones, those with medial origins, undergoes a biphasic dispersion: an early phase of mediolateral dispersion and a late phase of anteroposterior dispersion. This novel pattern of clonal dispersion suggests that the cerebellar VZ is not partitioned into parasagittal domains of lineage restriction. It leaves open the possibility that the later dispersion along the anteroposterior axis results from the parasagittal patterns of gene expression in the developing cerebellar cortex
Cell Migration and Chick Limb Development: Chemotactic Action of FGF-4 and the AER

AbstractExperiments have been carried out to investigate the role of the apical ectodermal ridge (AER) and FGF-4 on the control of cell migration during limb bud morphogenesis. By coupling DiI cell labeling with ectopic implantation of FGF-4 microcarrier beads we have found that FGF-4 acts as a potent and specific chemoattractive agent for mesenchymal cells of the limb bud. The response to FGF-4 is dose dependent in both the number of cells stimulated to migrate and the distance migrated. The cell migration response to FGF-4 appears to be independent of the known inductive activity of FGF-4 on Shh gene expression. We investigated the role of the AER in controlling cell migration by characterizing the migration pattern of DiI-labeled subapical cells during normal limb outgrowth and following partial AER removal. Subapical cells within 75 μm of the AER migrate to make contact with the AER and are found intermingled with nonlabeled cells. Thus, the progress zone is dynamic with cells constantly altering their neighbor relationships during limb outgrowth. AER removal studies show that cell migration is AER dependent and that subapical cells redirect their path of migration toward a functional AER. These studies indicate that the AER has a chemoattractive function and regulates patterns of cell migration during limb outgrowth. Our results suggest that the chemoattractive activity of the AER is mediated in part by the production of FGF-4
The Role of kreisler in Segmentation during Hindbrain Development

AbstractThe mouse kreisler gene is expressed in rhombomeres (r) 5 and 6 during neural development and kreisler mutants have patterning defects in the hindbrain that are not fully understood. Here we analyzed this phenotype with a combination of genetic, molecular, and cellular marking techniques. Using Hox/lacZ transgenic mice as reporter lines and by analyzing Eph/ephrin expression, we have found that while r5 fails to form in these mice, r6 is present. This shows that kreisler has an early role in the formation of r5. We also observed patterning defects in r3 and r4 that are outside the normal domain of kreisler expression. In both heterozygous and homozygous kreisler embryos some r5 markers are induced in r3, suggesting that there is a partial change in r3 identity that is not dependent upon the loss of r5. To investigate the cellular character of r6 in kreisler embryos we performed heterotopic grafting experiments in the mouse hindbrain to monitor its mixing properties. Control experiments revealed that cells from even- or odd-numbered segments only mixed freely with themselves, but not with cells of opposite character. Transposition of cells from the r6 territory of kreisler mutants reveals that they adopt mature r6 characteristics, as they freely mix only with cells from even-numbered rhombomeres. Analysis of Phox2b expression shows that some aspects of later neurogenesis in r6 are altered, which may be associated with the additional roles of kreisler in regulating segmental identity. Together these results suggest that the formation of r6 has not been affected in kreisler mutants. This analysis has revealed phenotypic and mechanistic differences between kreisler and its zebrafish equivalent valentino. While valentino is believed to subdivide preexisting segmental units, in the mouse kreisler specifies a particular segment. The formation of r6 independent of r5 argues against a role of kreisler in prorhombomeric segmentation of the mouse hindbrain. We conclude that the mouse kreisler gene regulates multiple steps in segmental patterning involving both the formation of segments and their A-P identity
Expression of Pax-3 in the Lateral Neural Plate Is Dependent on a Wnt-Mediated Signal from Posterior Nonaxial Mesoderm

AbstractDuring early patterning of the vertebrate neuraxis, the expression of the paired-domain transcription factor Pax-3 is induced in the lateral portions of the posterior neural plate via posteriorizing signals emanating from the late organizer and posterior nonaxial mesoderm. Using a dominant-negative approach, we show in explant assays that Pax-3 inductive activities from the organizer do not depend on FGF, retinoic acid, or XWnt-8, either alone or in combination, suggesting that the organizer may produce an unknown posteriorizing factor. However, Pax-3 inductive signals from posterior nonaxial mesoderm are Wnt-dependent. We show that Pax-3 expression in the lateral neural plate expands in XWnt-8-injected embryos and is blocked by dominant-negative XWnt-8. Similarly, we show that the homeodomain transcription factor Msx-1, which like Pax-3 is an early marker of the lateral neural plate, is induced by posterior nonaxial mesoderm and blocked by dominant-negative XWnt-8. Finally, we show that Rohon–Beard primary neurons, a cell type that develops within the lateral neural plate, are also blocked in vivo by dominant-negative Xwnt-8. Together these data support a model in which patterning of the lateral neural plate by Wnt-mediated signals is an early event that establishes a posteriolateral domain, marked by Pax-3 and Msx-1 expression, from which Rohon–Beard cells and neural crest will subsequently arise
Inhibition of Neural Crest Migration in Xenopus Using Antisense Slug RNA

AbstractBased primarily on studies in the chick, it has been assumed that the zinc finger transcription factor Slug is required for neural crest migration. In the mouse, however, Slug is not expressed in the premigratory neural crest, which forms normally in Slug −/− animals. To study the role of Slug in Xenopus laevis, we used the injection of XSlug antisense RNA and tissue transplantation. Injection of Slug antisense RNA did not suppress the early expression of the related gene XSnail, but led to reduced expression of both XSlug and XSnail in later stage embryos, whereas the expression of another neural crest marker, XTwist, was not affected. Down-regulation of XSlug and XSnail was associated with the inhibition of neural crest cell migration and the reduction or loss of many neural crest derivatives. In particular, the formation of rostral cartilages was often highly aberrant, whereas the posterior cartilages were less frequently affected. The effects of Slug antisense RNA on neural crest migration and cartilage formation were rescued by the injection of either XSlug or XSnail mRNA. These studies indicate that XSlug is required for neural crest migration, that XSlug and XSnail may be functionally redundant, and that both genes are required to maintain each other's expression in the neural crest development of xenopus laevis
Constitutive Activation of Sonic Hedgehog Signaling in the Chicken Mutant talpid2: Shh-Independent Outgrowth and Polarizing Activity

AbstractWe have examined the developmental properties of the polydactylous chicken mutant, talpid2. Ptc, Gli1, Bmp2, Hoxd13, and Fgf4 are expressed throughout the anteroposterior axis of the mutant limb bud, despite normal Shh expression. The expression of Gli3, Ihh, and Dhh appears to be normal, suggesting that the Shh signaling pathway is constitutively active in talpid2 mutants. We show that preaxial talpid2 limb bud mesoderm has polarizing activity in the absence of detectable Shh mRNA. When the postaxial talpid2 limb bud (including all Shh-expressing cells) is removed, the preaxial cells reform a normal-shaped talpid2 limb bud (regulate). However, a Shh-expressing region (zone of polarizing activity) does not reform; nevertheless Fgf4 expression in the apical ectodermal ridge is maintained. Such reformed talpid2 limb buds develop complete talpid2 limbs. After similar treatment, normal limb buds downregulate Fgf4, the preaxial cells do not regulate, and a truncated anteroposterior deficient limb forms. In talpid2 limbs, distal outgrowth is independent of Shh and correlates with Fgf4, but not Fgf8, expression by the apical ectodermal ridge. We propose a model for talpid2 in which leaky activation of the Shh signaling pathway occurs in the absence of Shh ligand
TGFβ-like Signaling and Spicule Development in Caenorhabditis elegans

AbstractA TGFβ-like signal is required for spicule development in Caenorhabditis elegans males. This signal appears to originate in the male-specific musculature and is required for the migrations of cells within the proctodeum. The migrations of these cells form cellular molds, the spicule traces, in which the cuticle of the spicules is secreted. Mutations in daf-4, sma-2, sma-3, and sma-4, which disrupt TGFβ-like signaling, result in aberrant migrations and morphologically abnormal spicules. daf-4, and hence the TGFβ-like signal, is required prior to or during cell migrations. Therefore, the TGFβ-like signal may act to prime the migrating cells or as a guidance cue. Mutations in lin-31 result in identical cell migration and spicule morphology defects. Thus, lin-31, which encodes a “winged helix” protein (Miller et al., Genes Dev. 7, 933–947, 1993), may be a component of this TGFβ-like signaling pathway