Genetic dissection of the glutamatergic neuron system in cerebral cortex

• Published in: Nature (London) Vol. 598; no. 7879; pp. 182 - 187
• Main Authors: Matho, Katherine S., Huilgol, Dhananjay, Galbavy, William, He, Miao, Kim, Gukhan, An, Xu, Lu, Jiangteng, Wu, Priscilla, Di Bella, Daniela J., Shetty, Ashwin S., Palaniswamy, Ramesh, Hatfield, Joshua, Raudales, Ricardo, Narasimhan, Arun, Gamache, Eric, Levine, Jesse M., Tucciarone, Jason, Szelenyi, Eric, Harris, Julie A., Mitra, Partha P., Osten, Pavel, Arlotta, Paola, Huang, Z. Josh
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.10.2021; Nature Publishing Group
• Subjects: 13; 14; 14/1; 14/19; 14/32; 14/35; 14/63; 14/69; 38; 42; 631/378; 631/378/2583; Animals; Cell fate; Cell Lineage - genetics; Cerebral cortex; Cerebral Cortex - cytology; Cerebral Cortex - metabolism; Channels; Cloning; Combinatorial analysis; Embryos; Gene expression; Gene Expression Regulation - genetics; Gene mapping; Glutamatergic transmission; Glutamic Acid - metabolism; Humanities and Social Sciences; Male; Mice; multidisciplinary; Neural stem cells; Neurogenesis; Neurons; Pattern formation; Pyramidal cells; Pyramidal Cells - classification; Pyramidal Cells - cytology; Pyramidal Cells - metabolism; Science; Science (multidisciplinary); Subpopulations; Temporal lobe; Transcription factors; Transcription Factors - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-021-03955-9

Diverse types of glutamatergic pyramidal neurons mediate the myriad processing streams and output channels of the cerebral cortex 1 , 2 , yet all derive from neural progenitors of the embryonic dorsal telencephalon 3 , 4 . Here we establish genetic strategies and tools for dissecting and fate-mapping subpopulations of pyramidal neurons on the basis of their developmental and molecular programs. We leverage key transcription factors and effector genes to systematically target temporal patterning programs in progenitors and differentiation programs in postmitotic neurons. We generated over a dozen temporally inducible mouse Cre and Flp knock-in driver lines to enable the combinatorial targeting of major progenitor types and projection classes. Combinatorial strategies confer viral access to subsets of pyramidal neurons defined by developmental origin, marker expression, anatomical location and projection targets. These strategies establish an experimental framework for understanding the hierarchical organization and developmental trajectory of subpopulations of pyramidal neurons that assemble cortical processing networks and output channels. A combination of genetic strategies and tools is used to define and fate-map different subtypes of glutamatergic pyramidal neurons according to their developmental and molecular programs, providing insight into the assembly of cortical processing networks.