PTEN is a critical genetic determinant of human ventricular size: Implications for hydrocephalus and autism spectrum disorder
Date of Award
Spring 2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Interdepartmental Neuroscience Program
First Advisor
Kahle, Kristopher
Abstract
The cerebrospinal fluid (CSF)-filled cerebral ventricles serve multiple poorly characterized functions critical for brain development. Ventriculomegaly (large ventricles) characterizes congenital hydrocephalus (CH) but is also associated with neurodevelopmental disorders, such as autism spectrum disorder (ASD). Here, we show de novo mutations in PTEN, one the most frequently mutated genes in ASD, are highly associated with CH. In the human brain PTEN is most highly expressed in fetal Nkx2.1+ neuroprogenitors in the subventricular zone of the medial ganglionic eminence. ASD- and CH-associated Pten mutation or conditional Pten deletion in fetal Nkx2.1+ neuroprogenitors phenocopies human ventriculomegaly in mice. Pten-mutant ventriculomegaly results from aqueductal stenosis secondary to Nkx2.1+ neuroprogenitor hyperproliferation and CSF hypersecretion due to inflammation-associated choroid plexus hyperplasia. Raptor deletion or post-natal everolimus ameliorates Pten-mutant ventriculomegaly by antagonizing mTORC1-dependent Nkx2.1+ cell pathology. These data show PTEN is a multimodal determinant of CSF homeostasis, ventricular size, and parenchymal brain function via its impact on neural stem cells. These results identify a potential non-surgical treatment for hydrocephalus and suggest ventriculomegaly could be a useful radiographic biomarker for ASD and other neurodevelopmental disorders.
Recommended Citation
DeSpenza, Tyrone, "PTEN is a critical genetic determinant of human ventricular size: Implications for hydrocephalus and autism spectrum disorder" (2023). Yale Graduate School of Arts and Sciences Dissertations. 985.
https://elischolar.library.yale.edu/gsas_dissertations/985
