Maintenance of neurotransmitter identity by Hox proteins through a homeostatic mechanism

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.

Cell context-dependent CFI-1/ARID3 functions control neuronal terminal differentiation

“…UNC-3 and the Hox proteins LIN-39 and MAB-5 are known terminal selectors in C. elegans nerve cord motor neurons. 45 , 46 , 58 , 59 As such, they are continuously required from embryonic to adult stages to activate expression of multiple terminal differentiation genes. 34 , 45 On the other hand, our constitutive (null alleles) and conditional (temporally controlled protein depletion) approaches also revealed a continuous requirement for CFI-1 in motor neurons ( Figure 4 ).…”