Similar Datasets
Project description:Neural stem cells (NSCs) in the prenatal neocortex progressively generate different subtypes of glutamatergic projection neurons. Following that, NSCs have a major switch in their progenitor properties and produce ?-aminobutyric acid (GABAergic) interneurons for the olfactory bulb (OB), cortical oligodendrocytes, and astrocytes. Herein, we provide evidence for the molecular mechanism that underlies this switch in the state of neocortical NSCs. We show that, at around E16.5, mouse neocortical NSCs start to generate GSX2-expressing (GSX2+) intermediate progenitor cells (IPCs). In vivo lineage-tracing study revealed that GSX2+ IPC population gives rise not only to OB interneurons but also to cortical oligodendrocytes and astrocytes, suggesting that they are a tri-potential population. We demonstrated that Sonic hedgehog signaling is both necessary and sufficient for the generation of GSX2+ IPCs by reducing GLI3R protein levels. Using single-cell RNA sequencing, we identify the transcriptional profile of GSX2+ IPCs and the process of the lineage switch of cortical NSCs.
| S-EPMC7197103 | biostudies-literature
Project description:Cortical Neural Stem Cell Lineage Progression Is Regulated by Extrinsic Signaling Molecule Sonic Hedgehog
| PRJNA591012 | ENA
Project description:Purpose:To asses changes in gene expression profiles from the P0 wild type littermate controls cortex, hGFAP-Cre, SmoM2f/+ mice cortex and ShhN IUE (ShhN palsmid were electroporated to wild type mice cortex at E13.5 and the cortex were dissected at P0) mice. Methords:Total RNA was isolated and sequenced using an illumina high-seq 2500. Raw data was analyzed using TopHat. Genes were considered significantly changed whicn perform fold-change>=2 and P value <= 0.05 Results: Compared to controls, 2466 genes were significantly down-regulated, and 5289 genes were up regulated in the RNA expression level of the SmoM2 mice; 3492 genes were significantly down-regulated, and 3577 genes were up regulated in the RNA expression level of the cortex of ShhN IUE mice.
2020-02-19 | GSE138878 | GEO
Project description:Purpose:To asses changes in gene expression profiles of single cell from the E16.5 wild type littermate controls cortex, and ShhN IUE (ShhN palsmid were electroporated to wild type mice cortex at E13.5 and the cortex were dissected at E16.5) mice. Methords: E16.5 wild type and ShhN-IUE cortices were carefully dissected under a fluorescent stereoscope, and incubated in 4 ml of papain solution for 20 min at 37℃, The cortical tissues were gently triturated, filtered through a 40 mm strainer, and washed with HBSS to obtain the single cell suspension. The Chromium droplet-based sequencing platform (10X Genomics) was used to generate scRNA-seq libraries, following the manufacturer’s instructions. The cDNA libraries were purified, quantified using Agilent 2100 Bioanalyzer, and sequenced on the Illumina Hiseq4000 Results: 7834 cells (2368 median genes per cell) captured for the Control cortex. And 8538 cells with 2422 median genes per cell captured for Shh-IUE mice.
2020-02-19 | GSE140816 | GEO
Project description:BackgroundFrem1 has been linked to human face shape variation, dysmorphology, and malformation, but little is known about its regulation and biological role in facial development.ResultsDuring midfacial morphogenesis in mice, we observed Frem1 expression in the embryonic growth centers that form the median upper lip, nose, and palate. Expansive spatial gradients of Frem1 expression in the cranial neural crest cell (cNCC) mesenchyme of these tissues suggested transcriptional regulation by a secreted morphogen. Accordingly, Frem1 expression paralleled that of the conserved Sonic Hedgehog (Shh) target gene Gli1 in the cNCC mesenchyme. Suggesting direct transcriptional regulation by Shh signaling, we found that Frem1 expression is induced by SHH ligand stimulation or downstream pathway activation in cNCCs and observed GLI transcription factor binding at the Frem1 transcriptional start site during midfacial morphogenesis. Finally, we found that FREM1 is sufficient to induce cNCC proliferation in a concentration-dependent manner and that Shh pathway antagonism reduces Frem1 expression during pathogenesis of midfacial hypoplasia.ConclusionsBy demonstrating that the Shh signaling pathway regulates Frem1 expression in cNCCs, these findings provide novel insight into the mechanisms underlying variation in midfacial morphogenesis.
| S-EPMC10066825 | biostudies-literature
Project description:Sonic Hedgehog (Shh) is a representative of the evolutionary closely related class of Hedgehog proteins that have essential signaling functions in animal development. The N-terminal domain (ShhN) is also assigned to the group of LAS proteins (LAS = Lysostaphin type enzymes, D-Ala-D-Ala metalloproteases, Sonic Hedgehog), of which all members harbor a structurally well-defined Zn2+ center; however, it is remarkable that ShhN so far is the only LAS member without proven peptidase activity. Another unique feature of ShhN in the LAS group is a double-Ca2+ center close to the zinc. We have studied the effect of these calcium ions on ShhN structure, dynamics, and interactions. We find that the presence of calcium has a marked impact on ShhN properties, with the two calcium ions having different effects. The more strongly bound calcium ion significantly stabilizes the overall structure. Surprisingly, the binding of the second calcium ion switches the putative catalytic center from a state similar to LAS enzymes to a state that probably is catalytically inactive. We describe in detail the mechanics of the switch, including the effect on substrate co-ordinating residues and on the putative catalytic water molecule. The properties of the putative substrate binding site suggest that ShhN could degrade other ShhN molecules, e.g. by cleavage at highly conserved glycines in ShhN. To test experimentally the stability of ShhN against autodegradation, we compare two ShhN mutants in vitro: (1) a ShhN mutant unable to bind calcium but with putative catalytic center intact, and thus, according to our hypothesis, a constitutively active peptidase, and (2) a mutant carrying additionally mutation E177A, i.e., with the putative catalytically active residue knocked out. The in vitro results are consistent with ShhN being a cannibalistic zinc-peptidase. These experiments also reveal that the peptidase activity depends on pH.
| S-EPMC4102407 | biostudies-literature
Project description:Interneurons in the cerebral cortex regulate cortical functions through the actions of distinct subgroups that express parvalbumin, somatostatin, or calretinin. The genesis of the first two subgroups requires the expression of NKX2.1, which is maintained by SHH signaling during neurogenesis. In this paper, we report that mosaic elimination in the medial ganglionic eminence (MGE) of Smo, a key effector of SHH signaling, reveals that MGE progenitors retain a remarkable degree of plasticity during the neurogenic period. SHH signaling prevents the upregulation of GSX2 and conversion of some MGE progenitors to a caudal ganglionic eminence-like, bipolar calretinin-expressing cell fate that is promoted by GSX2. In addition, a higher level of SHH signaling promotes the generation of the somatostatin-expressing interneuron at the expense of parvalbumin-expressing subgroup. These results indicate that cortical interneuron diversity, a major determinant of cortical function, is critically influenced by differential levels of SHH signaling within the ventral telencephalon.
| S-EPMC2868511 | biostudies-literature
Project description:The Hedgehog signaling pathway is essential for many aspects of normal embryonic development, including formation and patterning of the neural tube. Absence of the sonic hedgehog (shh) ligand is associated with the midline defect holoprosencephaly, whereas increased Shh signaling is associated with exencephaly and spina bifida. To complicate this apparently simple relationship, mutation of proteins required for function of cilia often leads to impaired Shh signaling and to disruption of neural tube closure. In this article, we review the literature on Shh pathway mutants and discuss the relationship between Shh signaling, cilia, and neural tube defects.
| S-EPMC3635124 | biostudies-literature
Project description:Regulating lineage progression of cortical neural stem cells by extrinsic signaling molecule SHH [bulk RNA-seq]
| PRJNA577670 | ENA
Project description:Throughout the developing nervous system, neural stem and progenitor cells give rise to diverse classes of neurons and glia in a spatially and temporally coordinated manner. In the ventral spinal cord, much of this diversity emerges through the morphogen actions of Sonic hedgehog (Shh). Interpretation of the Shh gradient depends on both the amount of ligand and duration of exposure, but the mechanisms permitting prolonged responses to Shh are not well understood. We demonstrate that Notch signaling plays an essential role in this process, enabling neural progenitors to attain sufficiently high levels of Shh pathway activity needed to direct the ventral-most cell fates. Notch activity regulates subcellular localization of the Shh receptor Patched1, gating the translocation of the key effector Smoothened to primary cilia and its downstream signaling activities. These data reveal an unexpected role for Notch shaping the interpretation of the Shh morphogen gradient and influencing cell fate determination.
| S-EPMC4449290 | biostudies-literature