Similar Datasets
Project description:Through microarray analyses of three SHH conditions, we were able to identify the miR-199 family as a family of miRNAs that is regulated by SHH signaling from the brain.
2020-09-21 | GSE144499 | GEO
Project description:miR-199 Family Regulates Sonic Hedgehog Expression During Craniofacial Development
| PRJNA603793 | ENA
Project description:miR-199 Family Regulates Sonic Hedgehog Expression During Craniofacial Development.
| PRJNA629570 | ENA
Project description:Mutations in SHH and several other genes encoding components of the Hedgehog signaling pathway have been associated with holoprosencephaly syndromes, with craniofacial anomalies ranging in severity from cyclopia to facial cleft to midfacial and mandibular hypoplasia. Studies in animal models have revealed that SHH signaling plays crucial roles at multiple stages of craniofacial morphogenesis, from cranial neural crest cell survival to growth and patterning of the facial primordia to organogenesis of the palate, mandible, tongue, tooth, and taste bud formation and homeostasis. This article provides a summary of the major findings in studies of the roles of SHH signaling in craniofacial development, with emphasis on recent advances in the understanding of the molecular and cellular mechanisms regulating the SHH signaling pathway activity and those involving SHH signaling in the formation and patterning of craniofacial structures.
| S-EPMC10529669 | biostudies-literature
Project description:Cilia assembly, maintenance and the localization of signal-transduction proteins necessitate a functioning intraflagellar transport (IFT). The IFT machinery moves cargo along a microtubule scaffold from the proximal to the distal end of the cilium. This anterograde transport is facilitated by a large multiprotein complex IFT-B, which consists of 16 proteins in total and recruits motor protein Kinesin-2 for active movement. TTC30A and TTC30B are integral components of this complex and were shown before to have redundant function in context of IFT. One paralogue could compensate the loss of the other, preventing the disruption of IFT-B and thus a severe ciliogenesis defect with no formation of the cilium. Affinity-based protein complex analysis of endogenously tagged cells, generated via CRISPR/Cas9 system as described before, revealed paralogue specific protein interactors proposing the involvement of TTC30A or TTC30B in other ciliary functions, particularly Sonic hedgehog signaling (Shh). Defects in this ciliary signaling pathway are often correlated to synpolydactyly, which intriguingly is also linked to a rare TTC30 variant. In this study we focus on the so far unknown interaction of TTC30A with protein kinase A catalytic subunit α PRKACA, which is a negative regulator of Shh pathway. For an in-depth analysis of this unique interaction and the influence on Shh, we used previously, via the CRISPR/Cas9 system, generated TTC30A or B single- and double-knockout hTERT-RPE1 cells as well as rescue cells harboring the TTC30 mutation. Our systematic approach revealed the paralogue specific influence of TTC30A KO and mutated TTC30A on the activity of PRKACA as well as the uptake of Smoothened into the cilium resulting in a downregulation of Sonic hedgehog signaling. Affinity-based protein complex analysis of wildtype versus mutated TTC30A or TTC30B uncovered differences in interaction pattern. These interactome alterations combined with Shh downregulation suggest a possible mechanism of how mutant TTC30A and respectively TTC30A KO are linked to synpolydactyly.
2024-01-26 | PXD044183 | Pride
Project description:Cancer genomics has illuminated a wide spectrum of genes and core molecular processes contributing to human malignancy. Still, the genetic and molecular basis of many cancers remains only partially explained. Genetic predisposition accounts for 5-10% of cancer diagnoses and genetic events cooperating with known somatic driver events are poorly understood. Analyzing established cancer predisposition genes in medulloblastoma (MB), a malignant childhood brain tumor, we recently identified pathogenic germline variants that account for 5% of all MB patients. Here, by extending our previous analysis to include all protein-coding genes, we discovered and replicated rare germline loss-of-function (LoF) variants across Elongator Complex Protein 1 (ELP1) on 9q31.3 in 15% of pediatric MBSHH cases, thus implicating ELP1 as the most common MB predisposition gene and increasing genetic predisposition to 40% for pediatric MBSHH. Inheritance was verified based on parent-offspring and pedigree analysis, which identified two families with a history of pediatric MB. ELP1-associated MBs were restricted to the molecular SHH subtype and were characterized by universal biallelic inactivation of ELP1 due to somatic loss of chromosome 9q. The majority of ELP1-associated MBs exhibited co-occurring somatic PTCH1 (9q22.32) alterations, suggesting that ELP1-deficiency predisposes to tumor development in combination with constitutive activation of SHH signaling. ELP1 is an essential subunit of the evolutionary conserved Elongator complex, whose primary function is to enable efficient translational elongation through tRNAs modifications at the wobble (U34) position. Biochemical, transcriptional, and proteomic analyses revealed that ELP1-associated MBSHH are characterized by a destabilized core Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response (UPR), consistent with deregulation of protein homeostasis due to Elongator-deficiency in model systems. Our findings suggest that genetic predisposition to proteome instability is a previously underappreciated determinant in the pathogenesis of pediatric brain cancer. These results provide strong rationale for further investigating the role of protein homeostasis in other pediatric and adult cancer types and potential opportunities for novel therapeutic interference.
2020-04-23 | PXD016832 | Pride
Project description:Medulloblastoma is the most common malignant pediatric brain tumor, and mechanisms underlying its development are poorly understood. We identified recurrent amplification of the miR-17/92 polycistron proto-oncogene in 6% of pediatric medulloblastomas by high-resolution single-nucleotide polymorphism genotyping arrays and subsequent interphase fluorescence in situ hybridization on a human medulloblastoma tissue microarray. Profiling the expression of 427 mature microRNAs (miRNA) in a series of 90 primary human medulloblastomas revealed that components of the miR-17/92 polycistron are the most highly up-regulated miRNAs in medulloblastoma. Expression of miR-17/92 was highest in the subgroup of medulloblastomas associated with activation of the sonic hedgehog (Shh) signaling pathway compared with other subgroups of medulloblastoma. Medulloblastomas in which miR-17/92 was up-regulated also had elevated levels of MYC/MYCN expression. Consistent with its regulation by Shh, we observed that Shh treatment of primary cerebellar granule neuron precursors (CGNP), proposed cells of origin for the Shh-associated medulloblastomas, resulted in increased miR-17/92 expression. In CGNPs, the Shh effector N-myc, but not Gli1, induced miR-17/92 expression. Ectopic miR-17/92 expression in CGNPs synergized with exogenous Shh to increase proliferation and also enabled them to proliferate in the absence of Shh. We conclude that miR-17/92 is a positive effector of Shh-mediated proliferation and that aberrant expression/amplification of this miR confers a growth advantage to medulloblastomas.
2010-04-02 | GSE21166 | GEO
Project description:The unique mental abilities of humans are rooted in the immensely expanded and folded neocortex, which reflects the expansion of neural progenitors, especially basal progenitors including basalradial glia (bRGs, also called outer RGs) and intermediate progenitor cells (IPCs). Here, we show that constitutively active Shh signaling expanded basal progenitors and induced folding in the otherwise smooth mouse neocortex, whereas the loss of Shh signaling decreased the number of basal progenitors and the size of the neocortex. SHH signaling was strongly active in the human fetal neocortex but not in the mouse embryonic neocortex, and blocking SHH signaling in humancerebral organoids decreased the number of bRGs. Mechanistically, Shh signaling increased theinitial generation and self-renewal of bRGs as well as increasing IPC proliferation. Thus, robust SHH signaling in the human fetal neocortex may contribute to basal progenitor expansion and neocortical growth and folding.
2016-05-23 | GSE80958 | GEO
Project description:ObjectivesThe main objective of this study was to evaluate how an apparently minor anomaly of the sphenoid bone, observed in a haploinsufficient mouse model for Sonic Hedgehog (Shh), affects the growth of the adult craniofacial region. This study aims to provide valuable information to orthodontists when making decisions regarding individuals carrying SHH mutation.Materials and methodsThe skulls of embryonic, juvenile and adult mice of two genotypes (Shh heterozygous and wild type) were examined and measured using landmark-based linear dimensions. Additionally, we analysed the clinical characteristics of a group of patients and their relatives with SHH gene mutations.ResultsIn the viable Shh+/ - mouse model, bred on a C57BL/6J background, we noted the presence of a persistent foramen at the midline of the basisphenoid bone. This particular anomaly was attributed to the existence of an ectopic pituitary gland. We discovered that this anomaly led to premature closure of the intrasphenoidal synchondrosis and contributed to craniofacial deformities in adult mice, including a longitudinally shortened skull base. This developmental anomaly is reminiscent of that commonly observed in human holoprosencephaly, a disorder resulting from a deficiency in SHH activity. However, sphenoid morphogenesis is not currently monitored in individuals carrying SHH mutations.ConclusionHaploinsufficiency of Shh leads to isolated craniofacial skeletal hypoplasia in adult mouse. This finding highlights the importance of radiographic monitoring of the skull base in all individuals with SHH gene mutations.
| S-EPMC10982674 | biostudies-literature
Project description:Apaf1 is an evolutionarily conserved component of the apoptosome. In mammals, the apoptosome assembles when cytochrome c is released from mitochondria, binding Apaf1 in an ATP-dependent manner and activating caspase 9 to execute apoptosis. Here we identify and characterize a novel mouse mutant, yautja, and find it results from a leucine-to-proline substitution in the winged-helix domain of Apaf1. We show that this allele of Apaf1 is unique, as the yautja mutant Apaf1 protein is stable, yet does not possess apoptotic function in cell culture or in vivo assays. Mutant embryos die perinatally with defects in craniofacial and nervous system development, as well as reduced levels of apoptosis. We further investigated the defects in craniofacial development in the yautja mutation and found altered Sonic hedgehog (Shh) signaling between the prechordal plate and the frontonasal ectoderm, leading to increased mesenchymal proliferation in the face and delayed or absent ossification of the skull base. Taken together, our data highlight the time-sensitive link between Shh signaling and the regulation of apoptosis function in craniofacial development to sculpt the face. We propose that decreased apoptosis in the developing nervous system allows Shh-producing cells to persist and direct a lateral outgrowth of the upper jaw, resulting in the craniofacial defects we see. Finally, the novel yautja Apaf1 allele offers the first in vivo understanding of a stable Apaf1 protein that lacks a function, which should make a useful tool with which to explore the regulation of programmed cell death in mammals.
| S-EPMC3792442 | biostudies-literature