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Metabolic Decisions in Development and Disease | EK27


Concerted shift in early forebrain during neural tube closure in proteostasis and glucose metabolism is reflected in cerebrospinal fluid proteome


Mar 27, 2021 12:00am ‐ Mar 27, 2021 12:00am

Description

Concerted shift in early forebrain during neural tube closure in proteostasis and glucose metabolism is reflected in cerebrospinal fluid proteome Ryann M Fame 1, Morgan L Shannon 1, Kevin F Chau 1,2, Joshua P Head 1, Maria K Lehtinen 1,2 1 Department of Pathology, Boston Children’s Hospital, Boston, Massachusetts, 02115, USA, 2 Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, 02115, USA The process of neural tube closure (NTC) involves massive, coordinated cellular changes as central nervous system (CNS) progenitors transition from forebrain neurectodermal cells to specified neuroepithelial cells. Environmental and genetic factors interact to drive NTC and defects arise from dysregulation of these processes. Using mouse models, we found differential transcriptional signatures of forebrain precursors between embryonic days E8.5 and E10.5 (before vs. after neural tube closure). These signatures contribute to regulating ribosomal biogenesis and proteostasis during this critical period (Chau et al., 2018). We also demonstrate coordinated changes in metabolic machinery in forebrain precursors during this same developmental stage. Progenitor mitochondria showed structural changes, including transition from hallmarks of glycolytic cristae at E8.5, to more traditional morphology at E10.5. Accordingly, glucose usage shifted in progenitors such that they relied markedly less on glycolysis by E10.5 (Fame, et al., 2019). This metabolic shift was matched by the surrounding amniotic and cerebrospinal fluid proteomes, suggesting usefulness of fluid biopsies to monitor CNS metabolic maturation and the potential of long distance signaling through fluid metabolites. Gain- and loss-of-function studies enabled us to demonstrate that these large, coordinated changes in proteostasis and metabolism in forebrain precursors during NTC are largely dependent on the concurrent developmental downregulation of c-MYC in progenitors. Such tight co-regulation of proteostasis and metabolism during NTC informs the relationship between neural precursor fate restriction and metabolic shifts, with the potential to guide future studies linking maternal metabolic dysregulation (maternal diabetes/ obesity), progenitor maturation, hypoxia, fluid metabolites, and neural tube closure defects.

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