Developmental origins of neural diversity
In the last several years, new single-cell genomic methods have transformed our understanding of the mammalian brain, revealing extraordinary cellular diversity. Recent work including our own indicates the brain contains thousands of cell types: both neurons and glia exhibit extensive region-specific variation. Strikingly, these cell types appear to reflect their developmental origins. Developmental processes clearly have a lasting impact on the brain and play critical roles in genetic predisposition to disease.
Our group seeks to understand the emergence of neural diversity. We’re particularly interested in the brainstem, where our data reveal an especially high number of cell types. The brainstem underlies some of our most essential functions, playing a central role in neuropsychiatric and neurodegenerative disease. We ask questions like:
How do cell types in the brainstem diversify?
How do these processes interact with genetic mutations?
How does the human brain innovate on these processes?
We approach these questions with mouse models and high-throughput genomic technologies. Brain development is a complex process involving the generation and migration of many cells that arerapidly changing and communicating with one another. Single-cell methods have the potential to disentangle these processes, infer their interactions with genetic mutations, and explore how these forces have changed over the course of evolution.
We use single-cell technologies to investigate the emergence of cellular diversity in the mammalian brain.
Dr. Kimberly Siletti
- Siletti K, Hodge R, Mossi Albiach A, Lee KW, Ding SL, Hu L, Lönnerberg P, Bakken T, Casper T, Clark M, Dee N, Gloe J, Hirschstein D, Shapovalova NV, Keene CD, Nyhus J, Tung H, Yanny AM, Arenas E, Lein ES, Linnarsson S. Transcriptomic diversity of cell types across the adult human brain. . Science. 2023 Oct 13;382(6667):eadd7046. doi: 10.1016/j.xgen.2022.100107. Epub 2023 Oct 13. PMID: 37824663
- Tian W, Zhou J, Bartlett A, Zeng Q, Liu H, Castanon RG, Kenworthy M, Altshul J, Valadon C, Aldridge A, Nery JR, Chen H, Xu J, Johnson ND, Lucero J, Osteen JK, Emerson N, Rink J, Lee J, Li YE, Siletti K, Liem M, Claffey N, O’Connor C, Yanny AM, Nyhus J, Dee N, Casper T, Shapovalova N, Hirschstein D, Ding SL, Hodge R, Levi BP, Keene CD, Linnarsson S, Lein E, Ren B, Behrens MM, Ecker JR. Single-cell DNA methylation and 3D genome architecture in the human brain. Science. 2023 Oct 13;382(6667):eadf5357. doi: 10.1016/j.xgen.2022.100107. Epub 2023 Oct 13. PMID: 37824674; PMCID: PMC10572106.
- Luo C, Liu H, Xie F, Armand EJ, Siletti K, Bakken TE, Fang R, Doyle WI, Stuart T, Hodge RD, Hu L, Wang BA, Zhang Z, Preissl S, Lee DS, Zhou J, Niu SY, Castanon R, Bartlett A, Rivkin A, Wang X, Lucero J, Nery JR, Davis DA, Mash DC, Satija R, Dixon JR, Linnarsson S, Lein E, Behrens MM, Ren B, Mukamel EA, Ecker JR. Single nucleus multi-omics identifies human cortical cell regulatory genome diversity. Cell Genom. 2022 Mar 9;2(3):100107. doi: 10.1016/j.xgen.2022.100107. PMID: 35419551; PMCID: PMC9004682.
- BRAIN Initiative Cell Census Network (BICCN). A multimodal cell census and atlas of the mammalian primary motor cortex. Nature. 2021 Oct;598(7879):86-102. doi: 10.1038/s41586-021-03950-0. Epub 2021 Oct 6. PMID: 34616075; PMCID: PMC8494634.
- La Manno G, Siletti K, Furlan A, Gyllborg D, Vinsland E, Mossi Albiach A, Mattsson Langseth C, Khven I, Lederer AR, Dratva LM, Johnsson A, Nilsson M, Lönnerberg P, Linnarsson S. Molecular architecture of the developing mouse brain. Nature. 2021 Aug;596(7870):92-96. doi: 10.1038/s41586-021-03775-x. Epub 2021 Jul 28. PMID: 34321664.