KATNAL2 mutation cause hydrocephalus by impairing vesicular trafficking and ependymal cell polarity in ASD
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ABSTRACT:
PROVIDER: PRJNA1168536 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30874410_1.fastq.gz | Fastqsanger.gz | |||
| SRR30874410_2.fastq.gz | Fastqsanger.gz | |||
| SRR30874411_1.fastq.gz | Fastqsanger.gz | |||
| SRR30874411_2.fastq.gz | Fastqsanger.gz |
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Project description:Autism spectrum disorders (ASD) are characterized by intricate neurodevelopmental abnormalities, yet the molecular underpinnings remain elusive for many high-risk genes, including KATNAL2. Here, we identify KATNAL2 as a key regulator of the intracellular vesicular system in the ependymal epithelium, crucial for vesicle trafficking and ciliary function. We demonstrate that an ASD-associated mutation in KATNAL2 disrupts its molecular activity, impairing intracellular vesicle trafficking, which in turn alters planar cell polarity and ciliary motion in ependymal cells. These defects lead to compromised cerebrospinal fluid circulation and postnatal hydrocephalus in mice. Notably, ependymal-specific ablation of Katnal2 in neonatal mice recapitulated the hydrocephalic phenotype. Our findings uncover a previously unrecognized molecular role for the ASD risk gene KATNAL2 in ependymal cells, underscoring its essential function in vesicle trafficking and cell polarity regulation, and suggest new avenues for targeted therapeutic strategies for ASD.
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Project description:Defects in ependymal (E) cells, which line the ventricle and generate cerebrospinal fluid flow through ciliary beating, can cause hydrocephalus. Dishevelled genes (Dvls) are essential for Wnt signaling, and Dvl2 has been shown to localize to the rootlet of motile cilia. Using the hGFAP-Cre;Dvl1(-/-);2(flox/flox);3(+/-) mouse, we show that compound genetic ablation of Dvls causes hydrocephalus. In hGFAP-Cre;Dvl1(-/-);2(flox/flox);3(+/-) mutants, E cells differentiated normally, but the intracellular and intercellular rotational alignments of ependymal motile cilia were disrupted. As a consequence, the fluid flow generated by the hGFAP-Cre;Dvl1(-/-);2(flox/flox);3(+/-) E cells was significantly slower than that observed in control mice. Dvls were also required for the proper positioning of motile cilia on the apical surface. Tamoxifen-induced conditional removal of Dvls in adult mice also resulted in defects in intracellular rotational alignment and positioning of ependymal motile cilia. These results suggest that Dvls are continuously required for E cell planar polarity and may prevent hydrocephalus.
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Project description:Transcriptional profiling of the parietal cortex was performed in postnatal day 22 rats with obstructive hydrocephalus. An intracisternal injection of kaolin was done on postnatal day one, and severe hydrocephalus developed over 3 weeks. Hydrocephalic animals were compared to age-matched saline controls. The goal was to determine the effects of kaolin-induced neonatal hydrocephalus on gene expression.
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