Positive autofeedback regulation of Ptf1a transcription generates the levels of PTF1A required to generate itch circuit neurons
Open accessAbstract
Peripheral somatosensory input is modulated in the dorsal spinal cord by a network of excitatory and inhibitory interneurons. PTF1A is a transcription factor essential in dorsal neural tube progenitors for specification of these inhibitory neurons. Thus, mechanisms regulating Ptf1a expression are key for generating neuronal circuits underlying somatosensory behaviors. Mutations targeted to distinct cis-regulatory elements for Ptf1a in mice, tested the in vivo contribution of each element individually and in combination. Mutations in an autoregulatory enhancer resulted in reduced levels of PTF1A, and reduced numbers of specific dorsal spinal cord inhibitory neurons, particularly those expressing Pdyn and Gal. Although these mutants survive postnatally, at ∼3–5 wk they elicit a severe scratching phenotype. Behaviorally, the mutants have increased sensitivity to itch, but acute sensitivity to other sensory stimuli such as mechanical or thermal pain is unaffected. We demonstrate a requirement for positive transcriptional autoregulatory feedback to attain the level of the neuronal specification factor PTF1A necessary for generating correctly balanced neuronal circuits.
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These clusters correspond well with prior gene expression analysis of the postnatal spinal cord, including classic marker gene studies and three independent single nucleus sequencing datasets not included in the harmonized clustering.
“Second, these clusters correspond well with prior gene expression analysis of the postnatal spinal cord including many classic and well-established marker gene studies as well as three independent single nucleus sequencing datasets that were not included in the harmonized clustering: an independent dataset that we clustered separately and used to test the SeqSeek Classify algorithm, and two recent”
From A harmonized atlas of mouse spinal cord cell types and their spatial organization (2021) · cites this paper as [8]
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A harmonized atlas of mouse spinal cord cell types and their spatial organization
Russ, D. E., Cross, R. B. P., Li, L., Koch, S. C., Matson, K. J. E., Yadav, A., Alkaslasi, M. R., Lee, D. I., Le Pichon, C. E., Menon, V., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-25125-1 · Cited by 255 · see citing works
- Authors
- Mona, B., Villarreal, J., Savage, T. K., Kollipara, R. K., Boisvert, B. E., & Johnson, J. E.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2020-04-02
- Volume
- 34
- Issue
- 9-10
- Pages
- 621-636
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC7197352
- OpenAlex
- W3015127073
- Cited by
- 14
- References
- 60
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 2 · 2021: 3 · 2020: 1
- Type
- posted content
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Genes & Development (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Hamon Center for Regenerative Science and Medicine
- National Institutes of Health (R01 HD037932, R37 HD091856)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- Ptf1a, transcriptional autoregulation, positive feedback loop, pruritus, cis-regulatory elements, scratching behavior, prodynorphin, GAL, pain sensitivity
- MeSH terms
- Animals, Enhancer Elements, Genetic, Gene Expression Regulation, Mutation, Neurons, Pruritus, Spinal Cord, Transcription Factors, Feedback, Physiological, Mice, CRISPR-Cas Systems
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