André Sousa, PhD

Assistant Professor, Neuroscience

Biography

PhD, University of Porto, Portugal

Contact Information

Waisman Center
1500 Highland Ave
Room T509
Madison, WI 53706
andre.sousa@wisc.edu
Sousa Lab

Research Statement

The development of the human brain is a long and complex process that is precisely choreographed through tightly regulated transcriptional programs. Proper regulation of these programs is necessary for developing the numerous functionally distinct regions and cell types of the brain. Since the human brain exhibits morphological, physiological, and neural circuitry differences compared to other species, including other primates, it logically follows that many of these programs are human-specific. Due to both the evolutionarily distance from humans and the different social, cognitive, and motor abilities of classical model organisms, our capability to elucidate human-specific developmental programs has been limited, thus restricting our understanding of the human brain’s unique morphology, physiology, and connectivity. Importantly, uncovering this knowledge has far-reaching biomedical implications, as human-specific molecular and cellular mechanisms are involved not only in producing the most distinct aspects of human cognition and behavior, but also may underlie psychiatric and neurodevelopmental disorders.

Our lab aims to identify and characterize the molecular and cellular mechanisms that govern human brain development and evolution, and to apply that knowledge towards understanding neurodevelopmental and psychiatric disorders. To achieve this goal, we apply a multifaceted approach that combines:

Functional genomic studies to identify genes that are critical for proper neurodevelopment and have conserved or human-specific expression profiles. We are also interested in deciphering the regulatory logic of genes with human-specific expression profiles.
Developmental neurobiology studies that combine induced pluripotent stem (iPS) cells, mouse genetic models, and postmortem human and NHP brains to characterize the functions of those candidate genes in the development of the brain.
Molecular and cellular biology studies that inform the biological processes that are disrupted by alterations in those genes, particularly the ones that are associated with neurodevelopmental and neuropsychiatric disorders.

Selected Publications

Pubmed

West, N. R., Arachchilage, K. H., Knaack, S., MacGregor, S., Hosseini, M., Risgaard, R. D., Kumarage, P., Martinez, J. L., Zhang, S. C., Wang, D., Sousa, A. M. M., & Bhattacharyya, A. (2025). Single-nucleus analysis reveals oxidative stress in Down syndrome basal forebrain neurons at birth. Alzheimer’s & dementia : the journal of the Alzheimer’s Association, 21(7), e70445. https://doi.org/10.1002/alz.70445

Risgaard, R. D., Arachchilage, K. H., Knaack, S. A., Hosseini, M., Chen, R. J., Kumarage, P., Schmidt, D. K., Huang, X., Sheng, J., Wang, C. J., Giusti, E., Liu, S., Zhang, S. C., Wang, D., Bhattacharyya, A., & Sousa, A. M. M. (2025). Molecular and cellular processes disrupted in the early postnatal Down syndrome prefrontal cortex. bioRxiv : the preprint server for biology, 2025.06.30.662385. https://doi.org/10.1101/2025.06.30.662385

Gao, Y., Dong, Q., Arachchilage, K. H., Risgaard, R., Sheng, J., Syed, M., Schmidt, D. K., Jin, T., Liu, S., Knaack, S. A., Doherty, D., Glass, I., Levine, J. E., Wang, D., Chang, Q., Zhao, X., & Sousa, A. M. (2025). Multimodal analyses reveal genes driving electrophysiological maturation of neurons in the primate prefrontal cortex. Neuron, S0896-6273(25)00308-3. Advance online publication. https://doi.org/10.1016/j.neuron.2025.04.025

West NR, Arachchilage KH, Knaack S, Hosseini M, Risgaard RD, MacGregor S, Kumarage P, Martinez JL, Wang D, Sousa AMM, Bhattacharyya A. (2025). Single-nucleus analysis reveals dysregulated oxidative phosphorylation in Down syndrome basal forebrain at birth. bioRxiv [Preprint]. 2025 Feb 6:2025.02.05.636750. doi: 10.1101/2025.02.05.636750. PMID: 39975363; PMCID: PMC11839037.

Russo, M. L., Sousa, A. M. M., & Bhattacharyya, A. (2024). Consequences of trisomy 21 for brain development in Down syndrome. Nature reviews. Neuroscience, 25(11), 740–755. https://doi.org/10.1038/s41583-024-00866-2

Doll, H. M., Risgaard, R. D., Thurston, H., Chen, R. J., & Sousa, A. M. (2024). Evolutionary innovations in the primate dopaminergic system. Current opinion in genetics & development, 88, 102236. https://doi.org/10.1016/j.gde.2024.102236

Tao, Y., Li, X., Dong, Q., Kong, L., Petersen, A. J., Yan, Y., Xu, K., Zima, S., Li, Y., Schmidt, D. K., Ayala, M., Mathivanan, S., Sousa, A. M. M., Chang, Q., & Zhang, S. C. (2024). Generation of locus coeruleus norepinephrine neurons from human pluripotent stem cells. Nature biotechnology, 42(9), 1404–1416. https://doi.org/10.1038/s41587-023-01977-4

Sirois CL, Guo Y, Li M, Wolkoff NE, Korabelnikov T, Sandoval S, Lee J, Shen M, Contractor A, Sousa AMM, Bhattacharyya A, Zhao X. CGG repeats in the human FMR1 gene regulate mRNA localization and cellular stress in developing neurons. Cell Rep. 2024 Jun 25;43(6):114330. doi: 10.1016/j.celrep.2024.114330. Epub 2024 Jun 11. PMID: 38865241; PMCID: PMC11240841.

Sandoval, S. O., Cappuccio, G., Kruth, K., Osenberg, S., Khalil, S. M., Méndez-Albelo, N. M., Padmanabhan, K., Wang, D., Niciu, M. J., Bhattacharyya, A., Stein, J. L., Sousa, A. M. M., Waxman, E. A., Buttermore, E. D., Whye, D., Sirois, C. L., Cross-IDDRC Human Stem Cell Consortium, Williams, A., Maletic-Savatic, M., & Zhao, X. (2024). Rigor and reproducibility in human brain organoid research: Where we are and where we need to go. Stem cell reports, 19(6), 796–816. https://doi.org/10.1016/j.stemcr.2024.04.008

Shen, M., Sirois, C. L., Guo, Y., Li, M., Dong, Q., Méndez-Albelo, N. M., Gao, Y., Khullar, S., Kissel, L., Sandoval, S. O., Wolkoff, N. E., Huang, S. X., Xu, Z., Bryan, J. E., Contractor, A. M., Korabelnikov, T., Glass, I. A., Doherty, D., Birth Defects Research Laboratory, Levine, J. E., … Zhao, X. (2023). Species-specific FMRP regulation of RACK1 is critical for prenatal cortical development. Neuron, 111(24), 3988–4005.e11. https://doi.org/10.1016/j.neuron.2023.09.014

Klarić, T. S., Gudelj, I., Santpere, G., Novokmet, M., Vučković, F., Ma, S., Doll, H. M., Risgaard, R., Bathla, S., Karger, A., Nairn, A. C., Luria, V., Bečeheli, I., Sherwood, C. C., Ely, J. J., Hof, P. R., Sousa, A. M. M., Josić, D., Lauc, G., & Sestan, N. (2023). Human-specific features and developmental dynamics of the brain N-glycome. Science advances, 9(49), eadg2615. https://doi.org/10.1126/sciadv.adg2615

Singh, A. K., Allington, G., Viviano, S., McGee, S., Kiziltug, E., Ma, S., Zhao, S., Mekbib, K. Y., Shohfi, J. P., Duy, P. Q., DeSpenza, T., Jr, Furey, C. G., Reeves, B. C., Smith, H., Sousa, A. M. M., Cherskov, A., Allocco, A., Nelson-Williams, C., Haider, S., Rizvi, S. R. A., … Kahle, K. T. (2023). A novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus. Brain : a journal of neurology, 147(4), 1553–1570. https://doi.org/10.1093/brain/awad405brain/awad405

Guo, Y., Shen, M., Dong, Q., Méndez-Albelo, N. M., Huang, S. X., Sirois, C. L., Le, J., Li, M., Jarzembowski, E. D., Schoeller, K. A., Stockton, M. E., Horner, V. L., Sousa, A. M. M., Gao, Y., Birth Defects Research Laboratory, Levine, J. E., Wang, D., Chang, Q., & Zhao, X. (2023). Elevated levels of FMRP-target MAP1B impair human and mouse neuronal development and mouse social behaviors via autophagy pathway. Nature communications, 14(1), 3801. https://doi.org/10.1038/s41467-023-39337-0

Lear, B. P., Thompson, E. A. N., Rodriguez, K., Arndt, Z. P., Khullar, S., Klosa, P. C., Lu, R. J., Morrow, C. S., Risgaard, R., Peterson, E. R., Teefy, B. B., Bhattacharyya, A., Sousa, A. M. M., Wang, D., Benayoun, B. A., & Moore, D. L. (2023). Age-maintained human neurons demonstrate a developmental loss of intrinsic neurite growth ability. bioRxiv : the preprint server for biology, 2023.05.23.541995. https://doi.org/10.1101/2023.05.23.541995

He, C., Kalafut, N. C., Sandoval, S. O., Risgaard, R., Sirois, C. L., Yang, C., Khullar, S., Suzuki, M., Huang, X., Chang, Q., Zhao, X., Sousa, A. M. M., & Wang, D. (2023). BOMA, a machine-learning framework for comparative gene expression analysis across brains and organoids. Cell reports methods, 3(2), 100409. https://doi.org/10.1016/j.crmeth.2023.100409

Ma, S., Skarica, M., Li, Q., Xu, C., Risgaard, R. D., Tebbenkamp, A. T. N., Mato-Blanco, X., Kovner, R., Krsnik, Ž., de Martin, X., Luria, V., Martí-Pérez, X., Liang, D., Karger, A., Schmidt, D. K., Gomez-Sanchez, Z., Qi, C., Gobeske, K. T., Pochareddy, S., Debnath, A., … Sestan, N. (2022). Molecular and cellular evolution of the primate dorsolateral prefrontal cortex. Science (New York, N.Y.), 377(6614), eabo7257. https://doi.org/10.1126/science.abo7257

Giffin-Rao, Y., Sheng, J., Strand, B., Xu, K., Huang, L., Medo, M., Risgaard, K. A., Dantinne, S., Mohan, S., Keshan, A., Daley, R. A., Jr, Levesque, B., Amundson, L., Reese, R., Sousa, A., Tao, Y., Wang, D., Zhang, S. C., & Bhattacharyya, A. (2022). Altered patterning of trisomy 21 interneuron progenitors. Stem cell reports, 17(6), 1366–1379. https://doi.org/10.1016/j.stemcr.2022.05.001

Ozaydin, B., Bicki, E., Taparli, O. E., Sheikh, T. Z., Schmidt, D. K., Yapici, S., Hackett, M. B., Karahan-Keles, N., Eickhoff, J. C., Corcoran, K., Lagoa-Miguel, C., Guerrero Gonzalez, J., Dean Iii, D. C., Sousa, A. M. M., Ferrazzano, P. A., Levine, J. E., & Cengiz, P. (2022). Novel Injury Scoring Tool for Assessing Brain Injury following Neonatal Hypoxia-Ischemia in Mice. Developmental neuroscience, 44(4-5), 394–411. https://doi.org/10.1159/000525244

Duy, P. Q., Weise, S. C., Marini, C., Li, X. J., Liang, D., Dahl, P. J., Ma, S., Spajic, A., Dong, W., Juusola, J., Kiziltug, E., Kundishora, A. J., Koundal, S., Pedram, M. Z., Torres-Fernández, L. A., Händler, K., De Domenico, E., Becker, M., Ulas, T., Juranek, S. A., … Kahle, K. T. (2022). Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus. Nature neuroscience, 25(4), 458–473. https://doi.org/10.1038/s41593-022-01043-3

Franjic, D., Skarica, M., Ma, S., Arellano, J. I., Tebbenkamp, A., Choi, J., Xu, C., Li, Q., Morozov, Y. M., Andrijevic, D., Vrselja, Z., Spajic, A., Santpere, G., Li, M., Zhang, S., Liu, Y., Spurrier, J., Zhang, L., Gudelj, I., Rapan, L., … Sestan, N. (2022). Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells. Neuron, 110(3), 452–469.e14. https://doi.org/10.1016/j.neuron.2021.10.036

Girskis, K. M., Stergachis, A. B., DeGennaro, E. M., Doan, R. N., Qian, X., Johnson, M. B., Wang, P. P., Sejourne, G. M., Nagy, M. A., Pollina, E. A., Sousa, A., Shin, T., Kenny, C. J., Scotellaro, J. L., Debo, B. M., Gonzalez, D. M., Rento, L. M., Yeh, R. C., Song, J., Beaudin, M., … Walsh, C. A. (2021). Rewiring of human neurodevelopmental gene regulatory programs by human accelerated regions. Neuron, 109(20), 3239–3251.e7. https://doi.org/10.1016/j.neuron.2021.08.005

Shibata, M., Pattabiraman, K., Lorente-Galdos, B., Andrijevic, D., Kim, S. K., Kaur, N., Muchnik, S. K., Xing, X., Santpere, G., Sousa, A., & Sestan, N. (2021). Regulation of prefrontal patterning and connectivity by retinoic acid. Nature, 598(7881), 483–488. https://doi.org/10.1038/s41586-021-03953-x

Werling DM, Pochareddy S, Choi J, An JY, Sheppard B, Peng M, Li Z, Dastmalchi C, Santpere G, Sousa AMM, et al. (2020). Whole-Genome and RNA Sequencing Reveal Variation and Transcriptomic Coordination in the Developing Human Prefrontal Cortex. Cell Reports, 31(1):107489. doi: 10.1016/j.celrep.2020.03.053. PMID: 32268104

Vrselja Z, Daniele SG, Silbereis J, Talpo F, Morozov YM, Sousa AMM, Tanaka BS, Skarica M, Pletikos M, Kaur N, Zhuang ZW, Liu Z, Alkawadri R, Sinusas AJ, Latham SR, Waxman SG, Sestan N. (2019). Restoration of brain circulation and cellular functions hours post-mortem. Nature, 568(7752):336-343. doi: 10.1038/s41586-019-1099-1. Epub 2019 Apr 17. PMID: 30996318

Zhu Y, Sousa AMM, Gao T, Skarica M, Li M, Santpere G, Esteller-Cucala P, Juan D, Ferrández-Peral L, Gulden FO, Yang M, Miller DJ, Marques-Bonet T, Imamura Kawasawa Y, Zhao H, Sestan N.(2018). Spatiotemporal transcriptomic divergence across human and macaque brain development. Science, 362(6420):eaat8077. doi: 10.1126/science.aat8077. Epub 2018 Dec 13. PMID: 30545855

Amiri, A., Coppola, G., Scuderi, S., Wu, F., Roychowdhury, T., Liu, F., Pochareddy, S., Shin, Y., Safi, A., Song, L., Zhu, Y., Sousa, A., PsychENCODE Consortium, Gerstein, M., Crawford, G. E., Sestan, N., Abyzov, A., & Vaccarino, F. M. (2018). Transcriptome and epigenome landscape of human cortical development modeled in organoids. Science (New York, N.Y.), 362(6420), eaat6720. https://doi.org/10.1126/science.aat6720.

Sousa AMM, Zhu Y, Raghanti MA, Kitchen RR, Onorati M, Tebbenkamp ATN, Stutz B, Meyer KA, Li M, Kawasawa YI, Liu F, Perez RG, Mele M, Carvalho T, Skarica M, Gulden FO, Pletikos M, Shibata A, Stephenson AR, Edler MK, Ely JJ, Elsworth JD, Horvath TL, Hof PR, Hyde TM, Kleinman JE, Weinberger DR, Reimers M, Lifton RP, Mane SM, Noonan JP, State MW, Lein ES, Knowles JA, Marques-Bonet T, Sherwood CC, Gerstein MB, Sestan N. (2017). Molecular and cellular reorganization of neural circuits in the human lineage. Science, 358(6366):1027-1032. doi: 10.1126/science.aan3456. PMID: 29170230 Free

Sousa AMM, Meyer KA, Santpere G, Gulden FO, Sestan N. (2017). Evolution of the Human Nervous System Function, Structure, and Development. Cell, 170(2):226-247. doi: 10.1016/j.cell.2017.06.036. PMID: 28708995.

Onorati M, Li Z, Liu F, Sousa AMM, Nakagawa N, Li M, Dell’Anno MT, Gulden FO, Pochareddy S, Tebbenkamp ATN, Han W, Pletikos M, Gao T, Zhu Y, Bichsel C, Varela L, Szigeti-Buck K, Lisgo S, Zhang Y, Testen A, Gao XB, Mlakar J, Popovic M, Flamand M, Strittmatter SM, Kaczmarek LK, Anton ES, Horvath TL, Lindenbach BD, Sestan N. (2016). Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia. Cell Reports, 16(10):2576-2592. doi: 10.1016/j.celrep.2016.08.038. Epub 2016 Aug 24. PMID: 27568284

Pletikos M, Sousa AM, Sedmak G, Meyer KA, Zhu Y, Cheng F, Li M, Kawasawa YI, Sestan N. (2014). Temporal specification and bilaterality of human neocortical topographic gene expression. Neuron, 81(2):321-32. doi: 10.1016/j.neuron.2013.11.018. Epub 2013 Dec 26. PMID: 24373884.

Kwan KY, Lam MM, Johnson MB, Dube U, Shim S, Rašin MR, Sousa AM, Fertuzinhos S, Chen JG, Arellano JI, Chan DW, Pletikos M, Vasung L, Rowitch DH, Huang EJ, Schwartz ML, Willemsen R, Oostra BA, Rakic P, Heffer M, Kostović I, Judaš M, Sestan N. (2012). Species-dependent posttranscriptional regulation of NOS1 by FMRP in the developing cerebral cortex. Cell, 149(4):899-911. doi: 10.1016/j.cell.2012.02.060. PMID: 22579290.

Kang HJ, Kawasawa YI, Cheng F, Zhu Y, Xu X, Li M, Sousa AM, Pletikos M, Meyer KA, Sedmak G, Guennel T, Shin Y, Johnson MB, Krsnik Z, Mayer S, Fertuzinhos S, Umlauf S, Lisgo SN, Vortmeyer A, Weinberger DR, Mane S, Hyde TM, Huttner A, Reimers M, Kleinman JE, Sestan N. (2011). Spatio-temporal transcriptome of the human brain. Nature, 478(7370):483-9. doi: 10.1038/nature10523. PMID: 22031440