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

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

  • 期刊论文

  • 发表日期：

    2025年2月24日

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  • Tyrone DeSpenza Jr.,
  • Emre Kiziltug,
  • Garrett Allington,
  • Daniel G. Barson,
  • Stephen McGee,
  • David O’Connor,
  • Stephanie M. Robert,
  • Kedous Y. Mekbib,
  • Pranav Nanda,
  • Ana B. W. Greenberg,
  • Amrita Singh,
  • Phan Q. Duy,
  • Francesca Mandino,
  • Shujuan Zhao,
  • Anna Lynn,
  • Benjamin C. Reeves,
  • Arnaud Marlier,
  • Stephanie A. Getz,
  • Carol Nelson-Williams,
  • Hermela Shimelis,
  • Lauren K. Walsh,
  • Junhui Zhang,
  • Wei Wang,
  • Mackenzi L. Prina,
  • Annaliese OuYang,
  • Asan F. Abdulkareem,
  • Hannah Smith,
  • John Shohfi,
  • Neel H. Mehta,
  • Evan Dennis,
  • Laetitia R. Reduron,
  • Jennifer Hong,
  • William Butler,
  • Bob S. Carter,
  • Engin Deniz,
  • Evelyn M. R. Lake,
  • R. Todd Constable,
  • Mustafa Sahin,
  • Siddharth Srivastava,
  • Kellen Winden,
  • Ellen J. Hoffman,
  • Marina Carlson,
  • Murat Gunel,
  • Richard P. Lifton,
  • Seth L. Alper,
  • Sheng Chih Jin,
  • Michael C. Crair,
  • Andres Moreno-De-Luca,
  • Bryan W. Luikart,
  • Kristopher T. Kahle

摘要

Enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles (ventriculomegaly) is a defining feature of congenital hydrocephalus (CH) and an under-recognized 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+ neural progenitor 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 postnatal 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 nonsurgical treatment for CH, demonstrate a genetic association of ventriculomegaly and ASD, and help explain neurodevelopmental phenotypes refractory to CSF shunting in select individuals with CH.