Mandibulofacial dysostosis (MFD) is a human developmental disorder characterized by defects of the facial bones. It is the second most frequent craniofacial malformation after cleft lip and palate. Nager syndrome combines many features of MFD with a variety of limb defects. Mutations in SF3B4 (splicing factor 3b, subunit 4) gene, which encodes a component of the pre-mRNA spliceosomal complex, were recently identified as a cause for Nager syndrome, accounting for 60% of affected individuals. Nothing is known about the cellular pathogenesis underlying Nager type MFD. Here we describe the first animal model for Nager syndrome, generated by knocking down Sf3b4 function in Xenopus laevis embryos, using morpholino antisense oligonucleotides. Our results indicate that Sf3b4-depleted embryos show reduced expression of the neural crest genes sox10, snail2 and twist at the neural plate border, associated with a broadening of the neural plate. This phenotype can be rescued by injection of wild-type human SF3B4 mRNA but not by mRNAs carrying mutations that cause Nager syndrome. At the tailbud stage, morphant embryos had decreased sox10 and tfap2a expression in the pharyngeal arches, indicative of a reduced number of neural crest cells. Later in development, Sf3b4-depleted tadpoles exhibited hypoplasia of neural crest-derived craniofacial cartilages, phenocopying aspects of the craniofacial skeletal defects seen in Nager syndrome patients. With this animal model we are now poised to gain important insights into the etiology and pathogenesis of Nager type MFD, and to identify the molecular targets of Sf3b4.
All cranial placode progenitors arise from a common precursor field anterior to the neural plate, the pre-placodal region (PPR). We showed that transcription factor Zic1, expressed at the anterior neural plate, is necessary and sufficient to promote placode fate. Here we reveal a non-cell autonomous activity of Zic1 and implicate retinoic acid (RA) signaling as a key player in cranial placode progenitor specification. In a screen for genes activated by Zic1 we identify several factors involved in RA metabolism and function. Among them we show that retinaldehyde dehydrogenase 2 (RALDH2) and lipocalin-type prostaglandin D2 synthase (LPGDS), which respectively regulate the synthesis and transport of RA, directly participate in the establishment of the PPR. We propose that RALDH2 and LPGDS induction by Zic1 at the anterior neural plate allows for the localized production and transport of RA, which in turn activates a cranial placode developmental program in neighboring cells.
Summary: Despite its tremendous complexity, the vertebrate nervous system emerges from a homogenous layer of neuroepithelial cells, the neural plate. Its formation relies on the time-and space-controlled progression of developmental programs. Apoptosis is a biological process that removes superfluous and potentially dangerous cells and is implemented through the activation of a molecular pathway conserved during evolution. Apoptosis and an unconventional function of one of its main effectors, caspase-3, contribute to the patterning and growth of the neuroepithelium. Little is known about the intrinsic and extrinsic cues controlling activities of the apoptotic machinery during development. The BarH-like (Barhl) proteins are homeodomain-containing transcription factors. The observations in Caenorhabditis elegans, Xenopus, and mice document that Barhl proteins act in cell survival and as cell type-specific regulators of a caspase-3 function that limits neural progenitor proliferation. In this review, we discuss the roles and regulatory modes of the apoptotic machinery in the development of the neural plate. We focus on the Barhl2, the Sonic Hedgehog, and the Wnt pathways and their activities in neural progenitor survival and proliferation. genesis 53:203-224, 2015. V C 2015 Wiley Periodicals, Inc.
Little is known about the respective contributions of cell proliferation and cell death to the control of vertebrate forebrain growth. The homeodomain protein barhl2 is expressed in the diencephalons of Xenopus, zebrafish, and mouse embryos, and we previously showed that Barhl2 overexpression in Xenopus neuroepithelial cells induces Caspase3-dependent apoptosis. Here, barhl2 is shown to act as a brake on diencephalic proliferation through an unconventional function of Caspase3. Depletion of Barhl2 or Caspase3 causes an increase in diencephalic cell number, a disruption of the neuroepithelium architecture, and an increase in Wnt activity. Surprisingly, these changes are not caused by decreased apoptosis but instead, are because of an increase in the amount and activation of β-catenin, which stimulates excessive neuroepithelial cell proliferation and induces defects in β-catenin intracellular localization and an up-regulation of axin2 and cyclinD1, two downstream targets of β-catenin/T-cell factor/lymphoïd enhancer factor signaling. Using two different sets of complementation experiments, we showed that, in the developing diencephalon, Caspase3 acts downstream of Barhl2 in limiting neuroepithelial cell proliferation by inhibiting β-catenin activation. Our data argue that Bar homeodomain proteins share a conserved function as cell typespecific regulators of Caspase3 activities.cell-cycle | zona limitans intrathalamica | neuroarchitecture | apical T he forebrain (telencephalon and diencephalon) is derived from the most anterior part of the neural plate. Whereas the telencephalon grows rapidly during development, the diencephalon grows less, and its allosteric growth pattern plays a part in the formation of the zona limitans intrathalamica (ZLI), an important secondary brain organizer that secretes Sonic hedgehog (Shh; reviewed in refs. 1 and 2). Although much is known about the molecular processes underlying the acquisition of regional identity in the developing forebrain, little is known about how the differential growth of these subdomains is controlled.In general, the growth of a developing tissue depends on cell growth and proliferation counterbalanced by programmed cell death, usually apoptosis (reviewed in ref.3). Targeted disruption of one intracellular effector of the apoptotic pathway Caspase3 (Casp3) causes a decrease in apoptosis in the developing central nervous system (CNS), which is associated with hyperplasia of the ventricular and/or mantle zone and disorganization of the brain (4; reviewed in refs. 5 and 6). Caspases, however, function in processes other than apoptosis (reviewed in ref. 7). A nonapoptotic role for Casp3 in the regulation of cell proliferation and differentiation is suggested by its ability to cleave substrates associated with cell-cycle control and to finely tune mitogenic pathways (reviewed in ref. 7; 8, 9). Such observations raise the possibility that Casp3 may have nonapoptotic functions in neuroepithelial cells, where it might help control the proliferation and differentiation o...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.