MassIVE MSV000094549

Complete Public PXD051469

Suppression of astrocyte BMP signaling improves fragile X syndrome molecular signatures and functional deficits

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Description

Fragile X syndrome (FXS) is a monogenic (gene = Fmr1) neurodevelopmental disorder with complex and variable manifestations spanning molecular, neuroanatomical, and behavioral changes. Prior work shows astrocytes and their secreted proteins may contribute to the pathophysiology of FXS, and that the bone morphogenetic protein (BMP) pathway may underlie some of these changes. A conditional knock out (KO) of Smad4 in astrocytes suppresses BMP signaling and lessens the severity of Fmr1 KO audiogenic seizures. Using in vivo transcriptomic and proteomic profiling of astrocytes in the mouse cortex, we find hypermetabolic gene expression programs and downregulated secretory machinery and secreted proteins in Fmr1 KO astrocytes that are moderated by Smad4 cKO. Critically, astrocyte Smad4 conditional KO restores deficits in Fmr1 KO auditory cortex inhibitory synaptic density. Thus, astrocytes can contribute to Fmr1 KO molecular and functional phenotypes, and targeting astrocytes can mitigate FXS symptoms. [doi:10.25345/C5GB1XT70] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Fragile X syndrome (FXS) ; astrocyte ; bone morphogenetic protein (BMP) signaling ; proteomics ; secreted proteins ; transcriptomics

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Principal Investigators:
(in alphabetical order) 		Nicola J. Allen, Salk Institute for Biological Studies, USA
Submitting User: jdiedrich
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