Emerging Roles for Hox Proteins in the Last Steps of Neuronal Development in Worms, Flies, and Mice

Abstract

A remarkable diversity of cell types characterizes every animal nervous system. Previous studies provided important insights into how neurons commit to a particular fate, migrate to the right place and form precise axodendritic patterns. However, the mechanisms controlling later steps of neuronal development remain poorly understood. Hox proteins represent a conserved family of homeodomain transcription factors with well-established roles in anterior-posterior (A-P) patterning and the early steps of nervous system development, including progenitor cell specification, neuronal migration, cell survival, axon guidance and dendrite morphogenesis. This review highlights recent studies in Caenorhabditis elegans, Drosophila melanogaster and mice that suggest new roles for Hox proteins in processes occurring during later steps of neuronal development, such as synapse formation and acquisition of neuronal terminal identity features (e.g., expression of ion channels, neurotransmitter receptors, and neuropeptides). Moreover, we focus on exciting findings suggesting Hox proteins are required to maintain synaptic structures and neuronal terminal identity during post-embryonic life. Altogether, these studies, in three model systems, support the hypothesis that certain Hox proteins are continuously required, from early development throughout post-embryonic life, to build and maintain a functional nervous system, significantly expanding their functional repertoire beyond the control of early A-P patterning.

A molecular atlas of adult C. elegans motor neurons reveals ancient diversity delineated by conserved transcription factor codes

“…In C. elegans , Hox genes ceh-13 , lin-39 , mab-5 , and egl-5 are expressed both in developing and adult MNs ( Figure 2 ). 28 , 71 In mice, Hox genes are expressed in developing mouse MNs, 26 , 72 and we found that their expression persists into adulthood ( Figure 6C ). The sustained Hox expression, from embryo to adult, in specific MNs along the rostrocaudal axis points toward non-canonical roles in the adult nervous system.…”

The E3 ubiquitin ligase RNF220 maintains hindbrainHoxexpression patterns through regulation of WDR5 stability

“…In addition to their early roles in progenitor cell specification, cell survival, neuronal migration, axon guidance, and dendrite morphogenesis (Smith et al ., 2024.) , Hox genes also play key roles in the regulation of synapse formation, neuronal terminal identity and neural circuit assembly at late stages (Feng et al ., 2020; Feng et al ., 2021; Philippidou et al ., 2013.) .…”

“…At later stages, the Hox genes also play vital roles in neuronal migration and neural circuit formation (Feng et al ., 2021; Hockman et al ., 2019; Kratochwil et al ., 2017; X. Wang et al ., 2013.)…”

“…Hox factors are crucial for the specification, migration, cellular organization, and topographic input connectivity of PN neurons. Note that Hox gene expression is maintained up to postnatal and even adult stages in the hindbrain derivatives (Farago et al ., 2006; Feng et al ., 2021; Kratochwil et al ., 2017.) .…”

Diseased, differentiated and difficult: Strategies for improved engineering of in vitro neurological systems

“…Emerging evidence points to the action of HOX genes in regulating and maintaining post-mitotic and post-natal neural identity as well ( Feng et al, 2021 ), demonstrating that HOX expression is not only necessary for developmental patterning, but also strongly influences circuit connectivity and mature neural function. Osseward et al (2021) reported that a k-means clustering approach to divide lumbar neurons from newborn mice revealed that the first major division between neurons did not resolve into neurotransmitter identity, as expected, but instead divided sensory laminae I-III from HOXC10 expressing neurons in laminae IV-X involved in motor control and proprioception ( Osseward et al, 2021 ).…”