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 embryo through adulthood, in the nervous system. 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 (Hox transcriptional autoregulation counterbalanced by negative UNC-3 feedback) for homeostatic control of Hox gene expression in adult MNs. 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.

Widespread employment of conserved C. elegans homeobox genes in neuronal identity specification

“…Generally, HOX gene function has been well studied in early regionalization of the nervous system, e.g. in the spinal cord (Dasen and Jessell, 2009) or the hindbrain (Parker and Krumlauf, 2020), but it is only through recent analysis in both worms (this paper)(Feng et al, 2022; Feng et al, 2019; Kratsios et al, 2017; Zheng et al, 2015a; Zheng et al, 2015b) and mice (Catela et al, 2022) that late and likely continuous roles in neuron identity specification and maintenance have become apparent. Second, the TALE-type Meis/Pbx genes, which act as common cofactors for HOX cluster genes in many different cellular contexts (Mann et al, 2009), can have HOX-independent roles.…”