Continuous cell-type diversification in mouse visual cortex development
Yuan Gao, Cindy T. J. van Velthoven, Changkyu Lee, Eric D. Thomas, Rémi Mathieu, Angela Ayala, Stuard Barta, Darren Bertagnolli, Jazmin Campos, Trangthanh Pham, Daniel Carey, Tamara Casper, Anish Bhaswanth Chakka, Rushil Chakrabarty, Megan Chiang, Lindsey Ching, Michael Clark, Marie J. Desierto, Rebecca Ferrer, Jessica Gloe, Jeff Goldy, Nathan Guilford, Junitta Guzman, Carliana Halterman, Samantha D. Hastings, Daniel Hirschstein, Windy Ho, Katelyn James, Zoe Juneau, Naomi Martin, Rachel McCue, Emma Meyerdierks, Amanda Mitchell, Josh Nagra, Beagan Nguy, Thuc Nghi Nguyen, Paul Olsen, Alana Oyama, Nick Pena, Jacob S. Quon, Qingzhong Ren, Augustin Ruiz, Nadiya V. Shapovalova, Josef Šulc, Amy Torkelson, Alex Tran, Herman Tung, Nasmil Valera Cuevas, Justin Wang, Jeanelle Ariza, Delissa McMillen, Jack Waters, Michael Kunst, Kara Ronellenfitch, Boaz P. Levi, Michael Hawrylycz, Chelsea M. Pagan, Nick Dee, Kimberly A. Smith, Bosiljka Tasic, Zizhen Yao, Hongkui Zeng
Abstract
The mammalian cortex is composed of a highly diverse set of cell types and develops through a series of temporally regulated events1–3. Single-cell transcriptomics enables a systematic study of cell types across the entire timeline of cortical development. Here we present a comprehensive and high-resolution transcriptomic and epigenomic cell-type atlas of the developing mouse visual cortex. The atlas is built from a single-cell RNA sequencing dataset of 568,654 high-quality single-cell transcriptomes and a single-nucleus Multiome dataset of 200,061 high-quality nuclei, which were densely sampled across the embryonic and postnatal developmental stages (from embryonic day 11.5 to postnatal day 56). We computationally reconstructed a transcriptomic developmental trajectory map of all excitatory, inhibitory and non-neuronal cell types in the visual cortex. Branching points that mark the emergence of new cell types at specific developmental ages and molecular signatures of cellular diversification are identified. The trajectory map shows that neurogenesis, gliogenesis and early postmitotic maturation in the embryonic stage give rise to all cell classes and nearly all subclasses in a staggered parallel manner. Increasingly refined cell types emerge throughout the postnatal differentiation process, including the late emergence of many cell types during the eye-opening stage and the onset of critical period, suggesting that there is continuous cell-type diversification at different stages of cortical development. Throughout development, there are cooperative dynamic changes in gene expression and chromatin accessibility in specific cell types. We identify cell-type-specific and temporally resolved gene regulatory networks that link transcription factors and downstream target genes through accessible chromatin motifs. Collectively, our study provides a detailed dynamic molecular map directly associated with individual cell types and specific temporal events that can reveal the molecular logic underlying the complex and multifaceted cortical cell type and circuit development. A high-resolution transcriptomic and epigenomic cell-type atlas of the developing mouse visual cortex from embryonic to postnatal development is presented, providing a real-time dynamic molecular map associated with individual cell types and specific developmental events.