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Dissertation Defense: Developmental origins of cortical circuit dysfunction in a 22q11 deletion mouse model

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Shah Rukh

Dissertation Defense: Developmental origins of cortical circuit dysfunction in a 22q11 deletion mouse model

Shah Rukh

Graduate Student, Translational Biology, Medicine, and Health
Graduate Research Assistant, LaMantia Lab, Fralin Biomedical Research Institute at VTC
November 24, 2025, at 8 a.m.
Riverside 4, Room G101 A/B
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More About the Candidate and Project

Education

Virginia Tech, Translational Biology, Medicine, and Health, Ph.D. Candidate

Skolkovo Institute of Science and Technology, M.S.

National University of Sciences and Technology Pakistain, B.S., Biological Sciences

Training

Graduate Research Assistant, LaMantia Lab, Fralin Biomedical Research Institute at VTC

Mentors

Anthony LaMantia, Ph.D., Professor, Director of the Center for Neurobiology Research

Committee Members

  • Michael Fox, Ph.D., Dean, College of Natural Sciences, University of Massachusetts Amherst
  • Scott Johnstone, Ph.D., Assistant Professor, Fralin Biomedical Research Institute at VTC
  • Jia-Ray Yu, Ph.D., Assistant Professor, Fralin Biomedical Research Institute at VTC
  • Eva Anton, Ph.D., Professor, School of Medicine, University of North Carolina Chapel Hill
  • Ryan Purcell, Ph.D., Assistant Professor, Franlin Biomedical Research Institute at VTC

Publications

Rukh, S., Meechan, D. W., Siggins, C., Erwin, Z. D., Baldo, G., Peck, A., Maynard, T. M., & LaMantia, A.-S. (2025). 22q11 deletion selectively alters progenitor states and projection neuron identities in the developing cerebral cortex. BioRxiv (Cold Spring Harbor Laboratory). https://doi.org/10.1101/2025.05.12.653556

Rukh, S., Meechan, D. W., Maynard, T. M., & Lamantia, A. S. (2024). Out of Line or Altered States? Neural Progenitors as a Target in a Polygenic Neurodevelopmental Disorder. Developmental neuroscience, 46(1), 1–21. https://doi.org/10.1159/000530898



Kostyukevich, Y., Kitova, A., Zherebker, A., Rukh, S., & Nikolaev, E. (2019). Investigation of the archeological remains using ultrahigh resolution mass spectrometry. European journal of mass spectrometry (Chichester, England), 25(4), 391–396. https://doi.org/10.1177/1469066719840287

Stepanov, A. I., Putlyaeva, L. V., Besedovskaya, Z., Shuvaeva, A. A., Karpenko, N. V., Rukh, S., Gorbachev, D. A., Malyshevskaia, K. K., Terskikh, A. V., Lukyanov, K. A., & Gurskaya, N. G. (2024). Genetically encoded epigenetic sensors for visualization of H3K9me3, H3K9ac and H3K4me1 histone modifications in living cells. Biochemical and biophysical research communications, 733, 150715. https://doi.org/10.1016/j.bbrc.2024.150715

About this Dissertation

Cortical circuit development is regulated by tightly regulated programs of progenitor proliferation, neurogenesis, and neuronal maturation. Disruptions in these processes contribute to the cortical circuit pathology observed in neurodevelopmental disorders such as schizophrenia and autism, intellectual disability. The 22q11.2 deletion syndrome (22q11DS), a major genetic risk factor for psychiatric illness and provides an optimal genetic model disease to explore how gene dosage imbalance impacts cortical circuit development. Study 1 examined the developmental origin of upper layer 2/3 projection neuron (PNs) deficits in the LgDel mouse model of 22q11DS. Bulk and single cell RNA sequencing revealed transient, cell state dependent changes in intermediate basal progenitors at the peak of upper layer neurogenesis. These changes are characterized by reduced proliferation, increased neurogenic gene expression and altered DNA methylation. The divergent progenitor progression resulted in a selective decline as well shift in identity of L2/3 PNs generated during this critical developmental window, while earlier and later population of progenitors as well progeny remained unaffected. Study 2 investigated how 22q11 deletion alters L2/3 PN growth and development. LgDel neurons displayed oxidative stress, mitochondrial dysfunction, and reduced neurite growth. Treatment with the antioxidant N-acetylcysteine (NAC) improved axonal and dendritic growth but did not restore expression of deleted or differentially expressed genes in LgDel PNs. Instead, NAC induced a distinct antioxidant response via Nrf2 signaling pathway. Together, these studies link early transcriptional dysregulation in cortical progenitors to later metabolic and functional deficits in projection neurons, highlighting oxidative stress as a modifiable driver of cortical circuit dysfunction in 22q11DS.