Ptf1a determines GABAergic over glutamatergic neuronal cell fate in the spinal cord dorsal horn
Abstract
Mutations in the human and mouse PTF1A/Ptf1a genes result in permanent diabetes mellitus and cerebellar agenesis. We show that Ptf1a is present in precursors to GABAergic neurons in spinal cord dorsal horn as well as the cerebellum. A null mutation in Ptf1a reveals its requirement for the dorsal horn GABAergic neurons. Specifically, Ptf1a is required for the generation of early-born (dI4, E10.5) and late-born (dILA, E12.5)dorsal interneuron populations identified by homeodomain factors Lhx1/5 and Pax2. Furthermore, in the absence of Ptf1a, the dI4 dorsal interneurons trans-fate to dI5 (Lmx1b+), and the dILA to dILB (Lmx1b+;Tlx3+). This mis-specification of neurons results in a complete loss of inhibitory GABAergic neurons and an increase in the excitatory glutamatergic neurons in the dorsal horn of the spinal cord by E16.5. Thus, Ptf1a function is essential for GABAergic over glutamatergic neuronal cell fates in the developing spinal cord, and provides an important genetic link between inhibitory and excitatory interneuron development.
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A subset of cells from the dorsal dI4.6/dI6 lineages contributed to most ventral inhibitory populations.
“A subset of cells from the dorsal dI4.6/dI6 lineages contributed to most ventral inhibitory populations, which was unexpected though there have been reports of scattered dI4 Ptf1a-derived cells in the embryonic and perinatal ventral horn103,104, and the very small dI6 population is known to be ventrally located105–107.”
From A harmonized atlas of mouse spinal cord cell types and their spatial organization (2021) · cites this paper as [103]
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Self-citation
- Authors
- Glasgow, S. M., Henke, R. M., MacDonald, R. J., Wright, C. V. E., & Johnson, J. E.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Vanderbilt University (US)
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2005-12-15
- Volume
- 132
- Issue
- 24
- Pages
- 5461-5469
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- OpenAlex
- W2030148675
- Cited by
- 225
- References
- 37
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 12 · 2023: 8 · 2022: 6 · 2021: 9 · 2020: 8 · 2019: 9 · 2018: 6 · 2017: 12 · 2016: 14 · 2015: 11 · 2014: 10 · 2013: 28 · 2012: 14
- FWCI
- 3.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Development (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institutes of Health (1r01hd037032-01)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK42502)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD37032)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Health Sciences › Medicine › Surgery › Congenital gastrointestinal and neural anomalies
- Keywords
- Ptf1a, dorsal horn, GABAergic neurons, glutamatergic neurons, neuronal cell fate specification, dorsal interneurons, Lhx1, PAX2, Lmx1b, TLX3, cerebellar agenesis, diabetes mellitus
- MeSH terms
- Animals, Cell Differentiation, Cerebellum, gamma-Aminobutyric Acid, Interneurons, Mice, Mutant Strains, Mutation, Neurons, Transcription Factors, Homeodomain Proteins, Glutamic Acid, Cell Lineage, Posterior Horn Cells, Mice, PAX2 Transcription Factor
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