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Peer-reviewedCC BY-NC-ND 4.0Proceedings of the National Academy of Sciences of the United States of America

Ddx3x deficiency in mice impairs corticofugal motor circuits and causes motor deficits that are attenuated by early-life exercise

  • Lauren Dierdorff1,2,3,4,5,6
  • Ikrame El Khaldi1,2,4,5,6
  • Marta Garcia-Forn1,2,4,5,6
  • Wei Wang7
  • Jeronimo Lukin1,2,4,5,6
  • Corinne M. Smith1,2,3,4,5,6
  • Adele Mossa1,2,4,5,6
  • Zhuhao Wu7
  • Silvia De Rubeis1,2,4,5,6,8,9
9 affiliations
  1. 1Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029
  2. 2Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029
  3. 3Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029
  4. 4The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
  5. 5The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
  6. 6The Alper Center for Neural Development and Regeneration Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
  7. 7Helen & Robert Appel Alzheimer’s Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021
  8. 8Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
  9. 9Department of Graduate Education, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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Abstract

The X-linked RNA helicase DDX3X is a high-risk gene for autism spectrum disorder and intellectual disability primarily in females. Individuals with pathogenic variants in DDX3X have pervasive and often severe motor manifestations. Using mouse models, we studied the circuits underlying the motor phenotypes associated with Ddx3x deficiency and examined the feasibility of an early intervention to ameliorate motor trajectories. We show that Ddx3x controls both the development and later plasticity of motor circuits connecting the motor cortex with the pontine nuclei. Ddx3x haploinsufficiency during development affects the dendritic arborization of corticopontine neurons. Juvenile-onset Ddx3x loss in corticopontine neurons is sufficient to induce adult motor impairments overlapping with those caused by chemogenetic disruption of corticopontine circuits. Further, Ddx3x mutant mice engage corticopontine circuits in skilled motor tasks in a sex-dependent manner. Last, Ddx3x haploinsufficient female mice undergoing a juvenile motor intervention show long-lasting specific benefits in their adult motor function. Together, these findings establish Ddx3x as an essential regulator of corticopontine neuron development and function and provide an early motor intervention to ameliorate motor outcomes in a mouse model of DDX3X haploinsufficiency.

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Cite

BibTeXRIS
BibTeX
@article{dierdorff2026ddx3x,
  title = {{Ddx3x deficiency in mice impairs corticofugal motor circuits and causes motor deficits that are attenuated by early-life exercise}},
  author = {Lauren Dierdorff and Ikrame El Khaldi and Marta Garcia-Forn and Wei Wang and Jeronimo Lukin and Corinne M. Smith and Adele Mossa and Zhuhao Wu and Silvia De Rubeis},
  journal = {Proceedings of the National Academy of Sciences of the United States of America},
  year = {2026},
  month = oct,
  doi = {10.1073/pnas.2535732123},
  url = {https://doi.org/10.1073/pnas.2535732123},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Ddx3x deficiency in mice impairs corticofugal motor circuits and causes motor deficits that are attenuated by early-life exercise
AU  - Lauren Dierdorff
AU  - Ikrame El Khaldi
AU  - Marta Garcia-Forn
AU  - Wei Wang
AU  - Jeronimo Lukin
AU  - Corinne M. Smith
AU  - Adele Mossa
AU  - Zhuhao Wu
AU  - Silvia De Rubeis
PY  - 2026
DA  - 2026/10/29
JO  - Proceedings of the National Academy of Sciences of the United States of America
DO  - 10.1073/pnas.2535732123
UR  - https://doi.org/10.1073/pnas.2535732123
AB  - The X-linked RNA helicase DDX3X is a high-risk gene for autism spectrum disorder and intellectual disability primarily in females. Individuals with pathogenic variants in DDX3X have pervasive and often severe motor manifestations. Using mouse models, we studied the circuits underlying the motor phenotypes associated with Ddx3x deficiency and examined the feasibility of an early intervention to ameliorate motor trajectories. We show that Ddx3x controls both the development and later plasticity of motor circuits connecting the motor cortex with the pontine nuclei. Ddx3x haploinsufficiency during development affects the dendritic arborization of corticopontine neurons. Juvenile-onset Ddx3x loss in corticopontine neurons is sufficient to induce adult motor impairments overlapping with those caused by chemogenetic disruption of corticopontine circuits. Further, Ddx3x mutant mice engage corticopontine circuits in skilled motor tasks in a sex-dependent manner. Last, Ddx3x haploinsufficient female mice undergoing a juvenile motor intervention show long-lasting specific benefits in their adult motor function. Together, these findings establish Ddx3x as an essential regulator of corticopontine neuron development and function and provide an early motor intervention to ameliorate motor outcomes in a mouse model of DDX3X haploinsufficiency.
SN  - 0027-8424
SN  - 1091-6490
ER  -