The secreted ligand Sonic Hedgehog (Shh) organizes the pattern of cellular differentiation in the ventral neural tube. For the five neuronal subtypes, increasing levels and durations of Shh signaling direct progenitors to progressively more ventral identities. Here we demonstrate that this mode of action is not applicable to the generation of the most ventral cell type, the nonneuronal floor plate (FP). In chick and mouse embryos, FP specification involves a biphasic response to Shh signaling that controls the dynamic expression of key transcription factors. During gastrulation and early somitogenesis, FP induction depends on high levels of Shh signaling. Subsequently, however, prospective FP cells become refractory to Shh signaling, and this is a prerequisite for the elaboration of their identity. This prompts a revision to the model of graded Shh signaling in the neural tube, and provides insight into how the dynamics of morphogen signaling are deployed to extend the patterning capacity of a single ligand. In addition, we provide evidence supporting a common scheme for FP specification by Shh signaling that reconciles mechanisms of FP development in teleosts and amniotes.
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http://dx.doi.org/10.1101/gad.559910 | DOI Listing |
Congenit Anom (Kyoto)
December 2024
Department of Molecular Craniofacial Embryology and Oral Histology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
Sonic hedgehog (Shh) is expressed in the oropharyngeal epithelium, including the frontonasal ectodermal zone (FEZ), which is defined as the boundary between Shh and Fgf8 expression domains in the frontonasal epithelium. To investigate the role of SHH signaling from the oropharyngeal epithelium, we generated mice in which Shh expression is specifically deleted in the oropharyngeal epithelium (Isl1-Cre; Shh). In the mutant mouse, Shh expression was excised in the oropharyngeal epithelium as well as FEZ and ventral forebrain, consistent with the expression pattern of Isl1.
View Article and Find Full Text PDFAdv Sci (Weinh)
December 2024
Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
There is an urgent necessity to devise efficient tactics to tackle the inevitable development of resistance to osimertinib, which is a third-generation epidermal growth factor receptor (EGFR) inhibitor used in treating EGFR-mutant nonsmall cell lung cancer (NSCLC). This study demonstrates that combining itraconazole with osimertinib synergistically reduces the proliferation and migration, enhances the apoptosis of osimertinib-resistant cells, and effectively inhibits the growth of osimertinib-resistant tumors. Mechanistically, itraconazole combined with osimertinib promotes the proteasomal degradation of sonic hedgehog (SHH), resulting in inactivation of the SHH/Dual-specificity phosphatase 13B (DUSP13B)/p-STAT3 and Hedgehog pathways, suppressing Myc proto-oncogene protein (c-Myc).
View Article and Find Full Text PDFAm J Physiol Cell Physiol
December 2024
Institute of Physiology, University Duisburg-Essen, Essen, Germany.
Over the last few decades, the primary cilium, an inconspicuous cell organelle, has increasingly become the focus of current research. The primary cilium is a microtubule-based, non-motile, antenna-like structure that is present on almost all mammalian cells. The ciliary membrane incorporates a large number of receptor molecules, which further characterize this cellular organelle.
View Article and Find Full Text PDFNon-syndromic orofacial clefts (NSOC) are common craniofacial birth defects, and result from both genetic and environmental factors. NSOC include three major sub-phenotypes: non-syndromic cleft lip with palate (NSCLP), non-syndromic cleft lip only (NSCLO) and non-syndromic cleft palate only (NSCPO), NSCLP and NSCLO are also sometimes grouped as non-syndromic cleft lip with or without cleft palate (NSCL/P) based on epidemiology. Currently known loci only explain a limited proportion of the heritability of NSOC.
View Article and Find Full Text PDFJ Oral Biosci
December 2024
Division of Anatomical and Cellular Pathology, Department of Pathology, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3694, Japan. Electronic address:
Objective: This study aimed to evaluate the role of the chromodomain helicase DNA-binding protein 3 (CHD3) in tooth morphogenesis in Chd3 knockout mice.
Methods: Chd3 knockout mice were generated using the CRISPR-Cas9 method. Mandibular first molars were extracted from the mice and their littermates and morphometrically analyzed.
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