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PTEN mutations impair CSF dynamics and cortical networks by dysregulating periventricular neural progenitors

ABSTRACT: Enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles (ventriculomegaly) is a defining feature of congenital hydrocephalus (CH) and an underrecognized concomitant of autism. Here, we show that de novo mutations in the autism risk gene, PTEN, are among the most frequent monogenic causes of CH and primary ventriculomegaly. Mouse Pten-mutant ventriculomegaly results from aqueductal stenosis due to hyperproliferation of periventricular Nkx2.1+ neuroprogenitor cells (NPCs) and increased CSF production from hyperplastic choroid plexus. Pten-mutant ventriculomegalic cortices exhibit network dysfunction from increased activity of Nkx2.1+ NPC-derived inhibitory interneurons. Raptor deletion or post-natal everolimus treatment corrects ventriculomegaly, rescues cortical deficits, and increases survival by antagonizing mTORC1-dependent Nkx2.1+ NPC pathology. Thus, PTEN mutations concurrently alter CSF dynamics and cortical networks by dysregulating Nkx2.1+ NPCs. These results implicate a non-surgical treatment for CH, demonstrate a genetic association of ventriculomegaly and ASD, and help explain neurodevelopmental phenotypes refractory to CSF shunting in select CH patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE280368 | GEO | 2025/04/01

REPOSITORIES: GEO

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Project description:PTEN Harmatoma Tumor Syndrome is a collection of clinical diagnosis with patients harbouring germline mutation in the PTEN gene. Most affected individuals have extreme macrocephaly and autism spectrum disorders were diagnosed in ~10% of the patients. However, the underpinning molecular mechanisms are not fully defined. The aim of this study is to compare the transcriptomic profiles of somatosensory cortices from Pten+/- and wild-type littermates (C57Bl6/J) of female and male at P30 and P42, primary neural cells, neuroprogenitor cells (NPCs), cortical astrocytes (PCA) and cortical neurons (PCN) from C57Bl6/J mice, with wild-type (WT as control for Pten+/- or CTRL as control for Nes-KO), heterozygous (Pten+/-)and complete knockout of Pten (Nes-KO). The study included performing RNA sequencing of these tissues and neural cells and integrating the data with human autism candidate genes (SFARI), and enrichment with GWAS genes for neurological diseases and traits. Methods: RNA sequencing of the somatosensory cortices and primary neural cells: Somatosensory cortices are cut from female and male mice at P30 and P42. NPCs are from E12.5 embryons. PCNs are from E15.5 embryos. PCAs are from P0 or P2 pups. Samples were lysed in TRIzol and RNA was extracted with chloroform/isopropanol and ethanol. Poly-A eniched RNA was used for library contruction. Results: We identified widespread signature genes in different samples, with enhanced immune response and oligodendrocyte development in somatosensory cortex, suppressed immediate early response genes in Pten+/- neurons, upregulated cilium components in astrocyte and downregulated inhibitory neurons in Pten knockout neural cells through RNA sequencing, which further enriched in GWAS genes of schizophrenia. Conclusion: Our study represents the first detailed comprehensive RNA-sequencing of somatosensory cortex and individual types of neural cells of transgenic mice with Pten heterozygous and homozygous knockout. The result suggested Pten effects on dysregulated immune response, immediately early response, cilium function and interneurons development which would direct further molecular studies on neuropathologenic mechanisms for PHTS.

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PTEN mutations impair CSF dynamics and cortical networks by dysregulating periventricular neural progenitors

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