Positive autofeedback regulation of Ptf1a transcription generates the levels of PTF1A required to generate itch circuit neurons

• Published in: Genes & development Vol. 34; no. 9-10; pp. 621 - 636
• Main Authors: Mona, Bishakha, Villarreal, Juan, Savage, Trisha K, Kollipara, Rahul K, Boisvert, Brooke E, Johnson, Jane E
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01.05.2020
• Subjects: Animals; CRISPR-Cas Systems; Enhancer Elements, Genetic - genetics; Feedback, Physiological - physiology; Gene Expression Regulation - physiology; Mice; Mutation; Neurons - cytology; Neurons - physiology; Pruritus - genetics; Research Paper; Spinal Cord; Transcription Factors - genetics; Transcription Factors - metabolism; itch; somatosensory; neuronal identity; transcriptional control; bHLH transcription factor; cell fate specification; inhibitory neuron; autoregulation; spinal cord development
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.332577.119

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 expression are key for generating neuronal circuits underlying somatosensory behaviors. Mutations targeted to distinct -regulatory elements for 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 and 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.