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<p>Coordination of cellular and physiological development by signaling is required for normal brain structure and function. Mutations in <i>OCRL</i>, a phosphatidylinositol 4,5 bisphosphate [PI(4,5)P<sub>2</sub>], 5-phosphatase leads to Lowe Syndrome (LS). However, the mechanism by which mutations in <i>OCRL</i> 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 <i>DLK1</i>, a Notch ligand in LS patient NSC associated increased levels of cleaved Notch and elevation of its transcriptional target <i>HES5</i>, indicating upregulated Notch signaling. Treatment of iPSC derived brain organoid with an inhibitor of PIP5K, the lipid kinase that synthesizes PI(4,5)P<sub>2</sub>, 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)P<sub>2</sub> dependent regulation of Notch signaling, cell fate specification and neuronal excitability regulated by OCRL.</p>

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Enhanced Notch dependent gliogenesis and delayed physiological maturation underlie neurodevelopmental defects in Lowe syndrome

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月11日

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  • Yojet Sharma,
  • Priyanka Bhatia,
  • Gagana Rangappa,
  • Sankhanil Saha,
  • Padinjat Raghu

摘要

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.