Genetic dissection of the glutamatergic neuron system in cerebral cortex
Open accessAbstract
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.
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Lhx2 and Lhx9 are co-expressed in thalamus and midbrain glutamatergic types, but Lhx2 is also specifically expressed in pallium IT-ET types.
“Lhx2 and Lhx9 are co-expressed in thalamus and midbrain glutamatergic types, but Lhx2 is also specifically expressed in the pallium IT–ET types108,109.”
From A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain (2023) · cites this paper as [108]
The Fate-mapping PyN progenitors > RGs section (page unavailable) reports Lhx2-positive progenitors in the dorsal pallium that give rise to IT and ET neurons. It does not establish that Lhx2 is specifically expressed in the IT–ET neuron types themselves, and a search for Lhx9 found no passage about its co-expression with Lhx2 in thalamic or midbrain glutamatergic types. (LLM, conf=0.87)
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- Authors
- Matho, K. S., Huilgol, D., Galbavy, W., He, M., Kim, G., An, X., Lu, J., Wu, P., Di Bella, D. J., Shetty, A. S., Palaniswamy, R., Hatfield, J., Raudales, R., Narasimhan, A., Gamache, E., Levine, J. M., Tucciarone, J., Szelenyi, E., Harris, J. A., Mitra, P. P., Osten, P., Arlotta, P., & Huang, Z. J.
- Affiliations
- Cold Spring Harbor Laboratory (US)
- Fudan University (CN)
- Shanghai Jiao Tong University (CN)
- Harvard University (US)
- Allen Institute for Brain Science (US)
- Broad Institute (US)
- Corresponding author
- Huang, Z. Josh
- ORCID
- 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
- Levine, Jesse M.
- Tucciarone, Jason
- Szelenyi, Eric
- Harris, Julie A.
- Mitra, Partha P.
- Osten, Pavel
- Arlotta, Paola
- Huang, Z. Josh
- Venue
- Nature
- Published
- 2021-10-06
- Volume
- 598
- Issue
- 7879
- Pages
- 182-187
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC8494647
- OpenAlex
- W3202866474
- Cited by
- 155
- References
- 72
- Citations by year
- 2026: 29 · 2025: 32 · 2024: 33 · 2023: 29 · 2022: 24 · 2021: 8
- FWCI
- 8.67
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Alliance for Research on Schizophrenia and Depression (26327)
- Cold Spring Harbor Laboratory
- National Institutes of Health (5u01mh114824-05, 1f31mh114529-01a1, 1s10od021759-01, MH114824, U01 MH114824-01)
- National Institute of Mental Health (U01 MH114824, U19MH114821, R01MH101268, F30MH097425, F31 MH114529, F30MH108333)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- cerebral cortex, cortical development, neural progenitor cells, dorsal telencephalon, fate mapping, transcription factors, neuronal differentiation
- MeSH terms
- Animals, Cerebral Cortex, Gene Expression Regulation, Male, Transcription Factors, Pyramidal Cells, Glutamic Acid, Cell Lineage, Mice
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