Cranial pericytes derived from neural crest cells reveal an inherent cell type-specific defect in Alzheimer's Disease
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ABSTRACT:
PROVIDER: PRJNA411796 | ENA |
REPOSITORIES: ENA
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Project description:Here, human pluripotent stem cells (including hiPSC and hESC) were induced to differentiate to pericytes (PCs) through the intermediate stage of cranial neural crest stem cells (NCSCs). We sequenced mRNA samples at different stages during NCSC-PCs differentiation of human pluripotent stem cells to generate the gene expression profiles of these cells.
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Project description:ADAMs are transmembrane metalloproteases that control cell behavior by cleaving both cell adhesion and signaling molecules. The cytoplasmic domain of ADAMs can regulate the proteolytic activity by controlling the subcellular localization and/or the activation of the protease domain. Here we show that the cytoplasmic domain of ADAM13 is cleaved and translocates into the nucleus. Preventing this translocation renders the protein incapable of promoting cranial neural crest (CNC) cell migration in vivo, without affecting its proteolytic activity. In addition, the cytoplasmic domain of ADAM13 regulates the expression of multiple genes in the CNC. This study shows that the cytoplasmic domain of ADAM metalloproteases can perform essential functions in the nucleus of cells and may contribute substantially to the overall function of the protein. Total RNA from cranial neural crest explants dissected from Xenopus laevis embryos at stage 15 to 17. Embryos were injected with either control morpholino (CMO), morpholino to ADAM13 (MO13) or MO13 and a fusion between GFP- and the cytoplasmic domain of ADAM13 (GFP-C13). Triplicate microarray correspond to independent experiments labeled DA4, DA5 and DA2. For each sample 1 is CMO, sample 2 is MO13 and sample 3 is MO13+C13. Embryos were injected with 10 ng of morpholino and 0.5 ng of GFP-C13 mRNA. Supplementary files: [1] matrix2_sig-genes.txt CNC array: Genes significantly affected by the loss of ADAM13 p<0.01. Normalized probe set generated by GC-RMA. [2] matrix3_sig-genes.txt CNC array: Genes significantly affected by the loss of ADAM13 and the addition of GFP-C13 p<0.01. Normalized probe set generated by GC-RMA.
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Project description:Developmental potential is progressively restricted after germ layer specification during gastrulation. However, cranial neural crest cells challenge this paradigm, as they develop from anterior ectoderm yet give rise to both mesodermal derivatives of the craniofacial skeleton and ectodermal derivatives of the peripheral nervous system. How cranial neural crest cells differentiate into multiple lineages is poorly understood. Here, we demonstrate that cranial neural crest cells possess a transient state of increased chromatin accessibility; and that the earliest premigratory neural crest are biased towards either a neuronal or ectomesenchymal fate, with each lineage expressing distinct factors from the pluripotent state. We profile the spatiotemporal emergence of each neural crest population and demonstrate that the ectomesenchymal lineage forms prior to the neuronal progenitors. Expression of the pluripotency microRNA family miR-302 is maintained in cranial neural crest cells and genetic deletion leads to precocious specification of the ectomesenchymal lineage. We find that miR-302 directly targets Sox9 to slow the timing of ectomesenchyme induction and regulates multiple genes involved in chromatin condensation to maintain accessibility for neuronal differentiation. Loss of mir-302 results in reduced chromatin accessibility in the neuronal progenitor lineage of neural crest and a reduction in peripheral neuron differentiation. Our findings reveal a post-transcriptional mechanism governed by miRNAs from pluripotency as an important mechanism to expand developmental potential of cranial neural crest.
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Project description:The cranial neural crest plays a fundamental role in orofacial development and morphogenesis. As a pluripotent and dynamic cell population, the cranial neural crest is undergoing vast transcriptional alterations throughout embryogenesis and the formation of facial structures. These transcriptional changes are regulated by several transcription factors and remodeling complexes. Previously, we revealed the relevance of the Ep400/Kat5 histone acetyltransferase complex in the cranial neural crest and showed that the knockout of Ep400 causes neural crest-related malformations such as orofacial clefting. Furthermore, a case study identified three patients carrying missense mutations in Kat5 who showed severe mental impairments as well as orofacial clefts.2 The exact molecular causes and mechanisms, however, are still unknown. In this study we selectively knocked out Ep400 or Kat5 in the murine cranial neural crest cell line O9-1 to examine its roles in neural crest biology. To understand the regulatory effects of Ep400 and Kat5, knockout neural crest cells were investigated via bulk RNA sequencing to unravel transcriptomic changes in the affected cells. Bioinformatic analyses hinted at the regulation of major cellular functions such as proliferation, ATP generation and protein synthesis by the Ep400/Kat5 complex. Reduced proliferation was confirmed by crystal violet staining, phospho-histone H3 staining and the determination of mitotic cells with condensed chromatin in vitro. We did not detect increased apoptosis in the knockout cell lines. The energetic profile of the cells was investigated by Seahorse technology. The ATP-rate assay showed a decreased glycolytic activity in Ep400- or Kat5-deficient cells. An O-propargyl-puromycin (OPP) Click-iT assay revealed a significant reduction in protein synthesis. To verify in vivo the discovered in vitro effects, Ep400 and Kat5 were selectively ablated in cranial neural crest using Wnt1-Cre in transgenic mice. The knockout of each of the subunits resulted in severe craniofacial malformations from E12.5 onwards. At E10.5 a significant reduction in neural crest-derived tissue and proliferation rate was evident. The strong defect in orofacial structures of mice lacking Kat5 or Ep400 completely correspond to the milder orofacial malformations in patients carrying heterozygous missense mutations. Our results furthermore argue that changes of metabolism, protein synthesis and proliferation in cranial neural crest cells are responsible for the orofacial defects observed in patients.
2023-03-23 | GSE215109 | GEO
Project description:The cranial neural crest (CNC) is a vertebrate-specific population that generates a huge diversity of derivatives, including the bulk of the connective and skeletal tissues of the head. How neural crest cells generate the appropriate cell types for distinct head regions over time remains unresolved. Here we profile RNA expression (scRNAseq) and chromatin accessibility (snATACseq) of the zebrafish cranial neural crest lineage at single-cell resolution from embryos to adults.
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