Department of Neurobiology, University of Chicago, Chicago, IL, USA.
University of Chicago Neuroscience Institute, Chicago, IL, USA.
Nat Commun. 2022 Oct 15;13(1):6097. doi: 10.1038/s41467-022-33781-0.
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.
Hox 转录因子在早期模式形成过程中发挥着基本作用，但它们也在神经系统中持续表达，从胚胎期到成年期。然而，其持续表达的功能意义尚不清楚。在秀丽隐杆线虫的运动神经元（MNs）中，我们发现 LIN-39（Scr/Dfd/Hox4-5）在胚胎后生命中持续需要维持神经递质特性，这是神经元功能的核心要素。LIN-39 直接作用于调节胆碱能特性（例如，unc-17/VAChT，cho-1/ChT）的基因。我们进一步表明，LIN-39、MAB-5（Antp/Hox6-8）和转录因子 UNC-3（Collier/Ebf）在正反馈回路中协同作用，以确保胆碱能特性基因的持续和强大表达。最后，我们确定了一种用于成人 MN 中 Hox 基因表达的自动平衡控制的双组分设计原则：Hox 转录自调节被负反馈的 UNC-3 平衡。这些发现揭示了 Hox 蛋白在胚胎后生命中的非典型作用，从早期模式形成到神经递质特性的控制，极大地扩展了它们的功能范围。
