Wnt activity reveals context-dependent genetic effects on gene regulation in neural progenitors
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PROVIDER: PRJNA1113718 | ENA |
REPOSITORIES: ENA
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Project description:Wnt activity reveals context-dependent genetic effects on gene regulation in neural progenitors
| PRJNA1113719 | ENA
Project description:Correct neural progenitor fate determination requires the coordination of extrinsic fate determinant signals with intrinsic responses. Post-translational modifications dynamically alter protein function and so are ideally situated to regulate development. Here we show that the deubiquitylaying enzyme, Usp9x modulates both intrinsic and extrinsic regulators of mouse neural progenitors. Nestin-cre mediated deletion of Usp9x from neural progenitors results in a transient disruption of cell adhesion and apical-basal polarity as well as the premature differentiation of intermediate neural progenitors. Ablation of Usp9x also significantly increased β-catenin protein levels, especially S33/S37/T41 phospho-β-catenin, and Wnt signalling. Usp9x was found to be part of the β-catenin destruction complex and loss of Usp9x affects destruction complex composition. Notch signalling was also increased in Usp9x ablated neural progenitors, coinciding with decreased Itch and Numb, and increased Notch intracellular domain protein levels. Usp9x co-localized and immunopreciptiated with Numb from neural progenitors suggesting it is required for Numb stabilisation. These data suggest Usp9x plays a role in coordinating intrinsic responses to extrinsic signals during neural development.
2017-08-18 | E-MTAB-4150 | biostudies-arrayexpress
Project description:Gene regulatory effects in bulk-post mortem brain tissues are undetected at many non-coding brain trait-associated loci. We hypothesized that context-specific genetic variant function during stimulation of a developmental signaling pathway would explain additional regulatory mechanisms. We measured chromatin accessibility and gene expression following activation of the canonical Wnt pathway in primary human neural progenitors from 82 donors. TCF/LEF motifs, brain structure-, and neuropsychiatric disorder-associated variants were enriched within Wnt-responsive regulatory elements (REs). Genetically influenced REs were enriched in genomic regions under positive selection along the human lineage. Stimulation of the Wnt pathway increased the detection of genetically influenced REs/genes by 66.2%/52.7%, and led to the identification of 397 REs primed for effects on gene expression. Context-specific molecular quantitative trait loci increased brain-trait colocalizations by up to 70%, suggesting that genetic variant effects during early neurodevelopmental patterning lead to differences in adult brain and behavioral traits.
| S-EPMC9934631 | biostudies-literature
Project description:KDM2B regulates hippocampal morphogenesis by transcriptionally silencing Wnt signaling in neural progenitors
| PRJNA922143 | ENA
Project description:Echinoderm microtubule (MT)-associated protein-like 1 (Eml1) is mutated in the HeCo mouse, which exhibits subcortical band heterotopia (SBH), a developmental malformation of the cerebral cortex. EML1 mutations are also found in human patients affected by severe ribbon-like heterotopia, associated with epilepsy and intellectual disability (1). Neural progenitors in the ventricular zone (VZ) of the developing cerebral cortex undergo precisely regulated divisions, and mitotic perturbations contribute to pathological mechanisms (2). Eml1 is expressed in the mouse VZ and ectopic progenitors are present in the mutant developing cortex, when Eml1 is absent, at early stages of development (1). Thus, Eml1 is likely to play a role in neural progenitors during cortical development. We performed cell and molecular biology assays aiming to elucidate the function of Eml1 in neural progenitors, and explored the VZ of the HeCo mutant in order to find morphological perturbations that might explain the initiation of SBH formation (3). As part of this study, we searched for Eml1 molecular partners by pull-downs from mouse cortical extracts at embryonic day E13.5 and mass spectrometry (MS) analyses in order to identify the molecular pathways in which the protein is involved (3). Eml1 is formed by an N-terminal region that contains a dimerization domain and a C-terminal region that forms a ‘tandem atypical propeller in EMLs’ (TAPE) domain. The isolated N-terminal domain strongly binds MTs, while the C-terminal domain preferentially binds tubulin, and its beta-propeller structure is thought also to mediate the interaction with other molecules (4,5). We focused for this study on the N-terminal part of the protein (amino acids 1-178). Future study will validate or elucidate new interactions by using the C-terminal domain and/or the full-length protein. The results obtained from the N terminal MS data, integrated with other experimental findings, allow us to insert Eml1 in a network of proteins that are likely to regulate the assembly and function of the mitotic spindle in neural progenitors (3). More precisely, we showed that the protein regulates MT dynamics and its loss leads to perturbations in metaphase spindle length, which in turn impact progenitor morphology and behavior (3). References 1. Kielar, M., et al. Mutations in Eml1 lead to ectopic progenitors and neuronal heterotopia in mouse and human. Nat. Neurosci. 17, 923–933 (2014). 2. Bizzotto, S., & Francis, F. Morphological and functional aspects of progenitors perturbed in cortical malformations. Front Cell Neurosci. 9, 30; 10.3389/fncel00030 (2015). 3. Bizzotto, S., et al. Eml1 loss impairs apical progenitor spindle length and soma shape in the developing cerebral cortex. 4. Richards, M. W., et al. Crystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypical β-propeller domain. Proc. Natl. Acad. Sci. U.S.A. 111, 5195–5200 (2014). 5. Richards, M. W., et al. Microtubule association of EML proteins and the EML4-ALK variant 3 oncoprotein require an N-terminal trimerization domain. Biochem. J. 467, 529–536 (2015).
2017-12-19 | PXD006837 | Pride
Project description:Schizophrenia is a complex and severe neuropsychiatric disorder, with a wide range of debilitating symptoms. Several aspects of its multifactorial complexity are still unknown, and some are accepted to be an early developmental deficiency with a more specifically neurodevelopmental origin. Understanding timepoints of disturbances during neural cell differentiation processes could lead to an insight into the development of the disorder. In this context, human brain organoids and neural cells differentiated from patient-derived induced pluripotent stem cells are of great interest as a model to study the developmental origins of the disease. Here we evaluated the differential expression of proteins of schizophrenia patient-derived neural progenitors, early neurons, and brain organoids. Using bottom-up shotgun proteomics with a label-free approach for quantitative analysis. Multiple dysregulated proteins were found in pathways related to synapses, in line with postmortem tissue studies of schizophrenia patients. However, organoids and immature neurons exhibit impairments in pathways never before found in patient-derived induced pluripotent stem cell studies, such as spliceosomes and amino acid metabolism. In conclusion, here we provide comprehensive, large-scale, protein-level data that may uncover underlying mechanisms of the developmental origins of schizophrenia.
2023-03-11 | PXD026593 | Pride
Project description:The modulation of WNT activity is critical for the specification of the anterior (head) tissue progenitors in the multipotent early epiblast and the repression of WNT activity enhances the ectoderm lineage potency of the epiblast cells and poises the activation of endogenous WNT activity that drives neurogenesis during head morphogenesis.
2019-03-31 | GSE103365 | GEO
Project description:KDM2B regulates hippocampal morphogenesis by transcriptionally silencing Wnt signaling in neural progenitors (ATAC-Seq)
| PRJNA922153 | ENA
Project description:KDM2B regulates hippocampal morphogenesis by transcriptionally silencing Wnt signaling in neural progenitors (ChIP-Seq)
| PRJNA922154 | ENA
Project description:KDM2B regulates hippocampal morphogenesis by transcriptionally silencing Wnt signaling in neural progenitors (RNA-Seq)
| PRJNA922155 | ENA