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CELLULAR AND DEVELOPMENTAL ORIGINS OF LOWE SYNDROME
Raghu Padinjatand 4 co-authors
National Centre for Biological Sciences-TIFR
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS05-09AM-372
Presentation
Date TBA
Board: PS05-09AM-372
Event Information
Poster Board
PS05-09AM-372
Poster
View posterAbstract
Coordination of cellular and physiological development by signaling is required for normal brain structure and function. Mutations in OCRL, a phosphatidylinositol 4,5 bisphosphate [PI(4,5)P2], 5-phosphatase leads to Lowe Syndrome (LS). However, the mechanism by which mutations in OCRL leads to the neurodevelopmental phenotypes of LS is not understood. We find that on differentiation of LS patient iPSC, neural cultures show reduced excitability and enhanced GFAP levels. Multiomic single-nucleus RNA and ATACseq analysis of neural stem cells revealed enhanced numbers of cells with a gliogenic cell state. Analysis of snRNA seq revealed increased levels of DLK1, a Notch ligand in LS patient NSC associated increased levels of cleaved Notch and elevation of its transcriptional target HES5, indicating upregulated Notch signaling. Treatment of iPSC derived brain organoid with an inhibitor of PIP5K, the lipid kinase that synthesizes PI(4,5)P2, was able to restore neuronal excitability and rescue Notch signaling defects in OCRL deficient organoids. Overall, our results demonstrate a role for PI(4,5)P2 dependent regulation of Notch signaling, cell fate specification and neuronal excitability regulated by OCRL.
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