The extracellular function of LGALS3BP in neural progenitors during brain development
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PROVIDER: PRJEB44886 | ENA |
REPOSITORIES: ENA
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Project description:This study demonstrates cellular and molecular mechanisms regulating the generation and function of basal radial glia (bRG), a neural stem cell population that was shown to be enriched in the developing human brain and was involved in the formation of cortical expansion. Here, we studied the role of LGALS3BP, a secreted protein whose RNA expression is enriched in bRGs. Based on a combination of three model systems i) in vitro human cerebral organoids, ii) ex vivo embryonic human fetal tissue and iii) in vivo embryonic mouse cortex, and a wide variety of techniques including single-cell RNA-sequencing, proteomics, and immunostaining, we characterized the role of human LGALS3BP mutations.
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Project description:Basal radial glial cells (bRGs) are neural progenitors enriched in primates and humans and were proposed to contribute to the expansion of neurons during cortical development in gyrencephalic species. Shortly after their generation, bRGs delaminate towards the outer subventricular zone, where they divide multiple times before differentiation. Thus, the regulation of bRGs generation could be essential for the establishment of correct gyrification within the human cortex. Here, we study the role of LGALS3BP, a secreted protein whose RNA expression is enriched in bRGs. By using cerebral organoids, human fetal tissues and mice, we show that manipulation of LGALS3BP regulated bRG generation. Additionally, individuals with unique de novo variants in LGALS3BP demonstrate abnormal gyrification and thickness at multiple sites over their cortex. Single-cell-RNA-sequencing and proteomics reveal the extracellular matrix involvement in the LGALS3BP mediated mechanisms. We find that LGALS3BP is required for bRGs delamination and influences corticogenesis and gyrification in humans.
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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).
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