Maintenance of neurotransmitter identity by Hox proteins through a homeostatic mechanism

Weidong Feng, Honorine Destain, Jayson J. Smith and Paschalis Kratsios ()
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Weidong Feng: University of Chicago
Honorine Destain: University of Chicago
Jayson J. Smith: University of Chicago
Paschalis Kratsios: University of Chicago

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Hox transcription factors play fundamental roles during early patterning, but they are also expressed continuously, from embryonic stages through adulthood, in the nervous system. However, the functional significance of their sustained expression remains unclear. In C. elegans motor neurons (MNs), we find that LIN-39 (Scr/Dfd/Hox4-5) is continuously required during post-embryonic life to maintain neurotransmitter identity, a core element of neuronal function. LIN-39 acts directly to co-regulate genes that define cholinergic identity (e.g., unc-17/VAChT, cho-1/ChT). We further show that LIN-39, MAB-5 (Antp/Hox6-8) and the transcription factor UNC-3 (Collier/Ebf) operate in a positive feedforward loop to ensure continuous and robust expression of cholinergic identity genes. Finally, we identify a two-component design principle for homeostatic control of Hox gene expression in adult MNs: Hox transcriptional autoregulation is counterbalanced by negative UNC-3 feedback. These findings uncover a noncanonical role for Hox proteins during post-embryonic life, critically broadening their functional repertoire from early patterning to the control of neurotransmitter identity.

Date: 2022
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DOI: 10.1038/s41467-022-33781-0

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