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At the Human Brain Development Lab, we study how the extraordinary diversity of cells and synapses in the brain is generated, organized, and maintained, and how these processes are disrupted in diseases such as neurodevelopmental disorders and brain cancer. By combining single-cell and spatial genomics, lineage tracing, perturbation screens, synaptic proteomics, and machine learning models, we aim to uncover the molecular rules that define neural identity and connectivity.
Our research spans two interrelated themes, each grounded in human biology and driven by cutting-edge technologies. By comparing these processes across species, we aim to uncover both conserved mechanisms and human-specific innovations that define the unique features of the human brain.
Theme I: Neural Stem Cell Lineages in Development and Brain Tumors
How do neural stem cells generate the full range of cell types in the human brain, and how is this process sustained into postnatal life? Our previous work established a single-cell multiomic atlas of the developing human neocortex, spanning from the first trimester to adolescence. This study revealed dynamic, cell-type-specific changes in transcription and chromatin accessibility, and enabled the inference of gene regulatory networks that are specific to developmental stage, cell type, and cortical area. Notably, we identified a previously under-characterized multipotent progenitor population with potential relevance to brain tumorigenesis.
Current projects include:
Fate Mapping of Human Neural Progenitors
We study the trajectories of stem and progenitor cells in the human brain, focusing on how they generate diverse neural lineages and persist into postnatal life. Through cross-species comparisons, we aim to uncover human-specific adaptations, elucidate the cellular logic of brain-building, and identify regenerative potential in the postnatal brain.Decoding Developmental Programs in Brain Tumors
Brain tumors often resemble specific neural lineages. We are mapping tumor heterogeneity and clonal evolution to identify the developmental hierarchies and stem-like states that fuel invasion, resistance, and recurrence.
Key publications:
Wang L*†, Wang C*, Moriano JA, Chen S, Zhang S, Mukhtar T, Wang S, Cebrián-Silla A, Bi Q, Augustin JJ, de Oliveira LG, Song M, Ge X, Zuo G, Paredes MF, Huang EJ, Alvarez-Buylla A, Duan X, Li J†, Kriegstein AR†. Molecular and cellular dynamics of the developing human neocortex. Nature. 2025 doi: https://doi.org/ 10.1038/s41586-024-08351-7. [Link]
Andrews MG*, Siebert C*, Wang L*, White ML, Ross J, Morales R, Donnay M, Bamfonga G, Mukhtar T, McKinney AA, Gemenes K, Wang S, Bi Q, Crouch EE, Parikshak N, Panagiotakos G, Huang EJ, Bhaduri A, Kriegstein AR. LIF signaling regulates outer radial glial to interneuron fate during human cortical development. Cell Stem Cell. 2023 Aug 29;S1934-5909(23)00292-8. [Link]
Pang K*, Wang L*, Wang W, Zhou J, Cheng C, Han K, Zoghbi HY, Liu Z. Coexpression enrichment analysis at the single-cell level reveals convergent defects in neural progenitor cells and their cell-type transitions in neurodevelopmental disorders. Genome Res. 2020 Jun;30(6):835-848. [Link]
Theme 2: Neural Communication and Synaptic Diversity in Development and Brain Tumors
The human brain forms highly specific synaptic connections, yet how this precision emerges and how synapses mature across development remain incompletely understood. To address this, we profiled over 1,000 synaptic proteins across cortical development in humans, macaques, and mice. This work uncovered three distinct stages of synapse maturation, each with selective vulnerability to disease. Notably, humans exhibited a delayed timeline of synapse development, partly driven by elevated Rho-GTPase signaling during the perinatal period. We also found that synaptic proteins are regulated in a cell-type-specific manner, indicating diverse molecular programs underlying synaptic identity. Intriguingly, neuron-to-glioma synapses appear to promote tumor proliferation and migration, pointing to a critical role for synaptic mechanisms in cancer progression.
Current projects include:
Mapping Synaptic Identity Across Development, Circuits, and Evolution
We are developing tools to isolate and analyze synapses with unprecedented specificity, aiming to uncover how synaptic composition varies across developmental stages, circuit identities, and species. In addition, we seek to identify the gene regulatory networks that govern these programs.Tumor-Neuron Synaptic Interactions
We are investigating how brain tumors form synaptic connections with neurons, characterizing their molecular and physiological features to identify new strategies for disrupting tumor-associated synaptogenesis.
Key publications:
Wang L†, Pang K, Zhou L, Cebrián-Silla A, González-Granero S, Wang S, Bi Q, White M, Ho B, Li J, Li T, Perez Y, Huang E, Winkler E, Paredes M, Kovner R, Sestan N, Pollen A, Liu P, Li J, Piao X, García-Verdugo J, Alvarez-Buylla A, Liu Z, Kriegstein AR†. A cross-species proteomic map of synapse development reveals neoteny during human postsynaptic density maturation. Nature. 2023 Oct;622(7981):112-119. [Link]
Wang L, Pang K, Han K, Adamski CJ, Wang W, He L, Lai JK, Bondar VV, Duman JG, Richman R, Tolias KF, Barth P, Palzkill T, Liu Z, Holder JL Jr, Zoghbi HY. An autism-linked missense mutation in SHANK3 reveals the modularity of Shank3 function. Mol Psychiatry. 2020 Oct;25(10):2534-2555. [Link]
Wang L, Adamski CJ, Bondar VV, Craigen E, Collette JR, Pang K, Han K, Jain A, Y Jung S, Liu Z, Sifers RN, Holder JL Jr, Zoghbi HY. A kinome-wide RNAi screen identifies ERK2 as a druggable regulator of Shank3 stability. Mol Psychiatry. 2020 Oct;25(10):2504-2516. [Link]
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