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Microglial GRB2 is essential for brain ventriculogenesis and CSF homeostasis

ABSTRACT: Microglia play essential yet poorly understood roles in brain development, including axon guidance, regulation of neurogenesis, and pruning of neuronal projections. Congenital hydrocephalus (CH), characterized by enlarged cerebrospinal fluid (CSF)-filled ventricles, is a leading cause of pediatric brain surgery, but its molecular mechanisms remain unclear. We have identified novel, recurrent, damaging missense variants in the SH3-binding domain of the adaptor protein Growth Factor Receptor-Bound Protein 2 (GRB2) in unrelated patients with CH. GRB2 is significantly co-expressed with one of its known upstream receptor tyrosine kinase partners, CSF1R, in the developing human brain, particularly in a microglial subtype associated with regulation of neural stem cells. Immunoprecipitation validated GRB2-CSF1R binding in mouse microglial cells and human monocytes. Cx3Cr1-Grb2fl/fl mice engineered with conditional deletion of Grb2 in microglia exhibit congenital absence of microglia and early postnatal severe communicating (non-obstructive) hydrocephalus, mimicking GRB2-mutant patients. The severe ventriculomegaly of Cx3Cr1-Grb2fl/fl mice is associated with both depletion of cerebral cortical neurons and impairment of glia-lymphatic-mediated CSF flow. Together, these findings implicate a novel role of GRB2 in microglia that could be essential for brain development and CSF homeostasis.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: TuKiet Lam

LAB HEAD: TuKiet Lam

PROVIDER: PXD081055 | Pride | 2026-07-14

REPOSITORIES: Pride

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			Action	DRS
	Herzog_GRB2-vs-WT_Total_S-trap_Ttest.mzML	Mzml
	Herzog_GRB2-vs-WT_Total_S-trap_Ttest.pdResult	Other
	QEp25-1220_Herzog_WT_1.msf	Msf
	QEp25-1220_Herzog_WT_1.raw	Raw
	QEp25-1226_Herzog_GRB2_2.msf	Msf

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