Research Goals

Ion channel Dysfunction Associated with Prenatal Diseases

Timeline of human gestation from early cortical formation, including key developmental cellular processes and milestones, highlighting the development of abundant action potentials in the cerebral cortex . Bottom, ion channel genes (ATP1A3, SCN3A, GRIN1, and GRIN2B) implicated in cortical malformations (MCDs) all maintain high expression in the developing human cortex . The specified genes are representative and are not a comprehensive list.

"Folded" Ferret brain model of human cortex development

Ferret neocortex recapitulates human disease (unpublished from microcephaly cases), a disease not able to me modeled in mice with smooth brains (lysencephalic).

To learn more about how our lab leverages the gyrencephalic ferret model to make insights to bran development and disease, see some recent work:

R.S. Smith, et al, (2018) “Sodium channel SCN3A (NaV1.3) regulation of human cerebral cortical folding and oral motor development”. Neuron. 1–17. PMCID: PMC6226006
M.B. Johnson,…R.S. Smith, 8 authors, C.A. Walsh & B.I. Bae (2018) “Aspm knockout ferret reveals an evolutionary mechanism governing cerebral cortical size” Nature. PMCID: PMC6095461
F.M. Krienen,..R.S. Smith, 12 authors, S.A. McCarroll (2020) “Innovations in Primate Interneuron Repertoire”. Nature. 586, 262–269. PMCPMC7957574
S. Barão, S.,… R.S. Smith, 8 authors, U. Müller. (2024) “Conserved transcriptional regulation by BRN1 and BRN2 in neocortical progenitors drives mammalian neural specification and neocortical expansion” Nat Commun. PMCID: PMC11399407

Using single cell technologies to understand disease pathology in the developing human brain

To learn more about how our lab leverages single cells to make insights to bran development and disease, see:

R.S. Smith*, M. Florio, S.K. Akula, J.E. Neil, Y. Wang, R.S. Hill, M. Goldman, N. Reed, L. Flores-Sarnet, A.J. Barkovich, J. Gonzalez-Heydrich, C.A. Brownstein, S.A. McCarroll, C.A. Walsh*. (2021) “Early role for a Na+/K+-ATPase (ATP1A3) in brain development”. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.2023333118. *Corresponding Author. PMCID: PMC8237684
R.S. Smith, et al, (2018) “Sodium channel SCN3A (NaV1.3) regulation of human cerebral cortical folding and oral motor development”. Neuron. 1–17. PMCID: PMC6226006
F.M. Krienen,..R.S. Smith, 12 authors, S.A. McCarroll (2020) “Innovations in Primate Interneuron Repertoire”. Nature. 586, 262–269. PMCPMC7957574

Leverging hIPSCs (2D and 3D) to model dysfunction associated with prenatal ion channel diseases and therapeutics

To learn more about how our lab leverages induced stem cells make insights to bran development and disease, see:

Golinski, S.R., Soriano, K., Briegel, A.C., Burke, M.C., Yu, T.W., Nakayama, T., Hu, R., and Smith, R.S.* (2024) “Gene therapy for targeting a prenatally enriched potassium channel associated with severe childhood epilepsy and premature death”. BioRxiv. Under Review. *Corresponding Author. https://doi.org/10.1101/2024.10.24.620125.
X Qian, EM DeGennaro, M Talukdar, SK Akula, A Lai, RS Smith, et al, C.A.Walsh (2022) Loss of non-motor kinesin KIF26A causes congenital brain malformations via dysregulated neuronal migration and axonal growth as well as apoptosis”. Developmental Cell. https://doi.org/10.1016/j.devcel.2022.09.011
M. Sudberg, H Pinson*, R.S. Smith*, K. Winden, P. Venugopal 1, D. Tai , J.F. Gusella, M.E. Talkowski, C.A. Walsh, M. Tegmark, M. Sahin, (2021) “RHOA inhibition rescues network hyperactivity of human iPSC-derived dopaminergic neurons with 16p11.2 deletion” Nat Commun 12, 2897 (2021). https://doi.org/10.1038/s41467-021-23113-z.