Brn3/POU‐IV‐type POU homeobox genes—Paradigmatic regulators of neuronal identity across phylogeny

Abstract

One approach to understand the construction of complex systems is to investigate whether there are simple design principles that are commonly used in building such a system. In the context of nervous system development, one may ask whether the generation of its highly diverse sets of constituents, that is, distinct neuronal cell types, relies on genetic mechanisms that share specific common features. Specifically, are there common patterns in the function of regulatory genes across different neuron types and are those regulatory mechanisms not only used in different parts of one nervous system, but are they conserved across animal phylogeny? We address these questions here by focusing on one specific, highly conserved and well‐studied regulatory factor, the POU homeodomain transcription factor UNC‐86. Work over the last 30 years has revealed a common and paradigmatic theme of unc‐86 function throughout most of the neuron types in which Caenorhabditis elegans unc‐86 is expressed. Apart from its role in preventing lineage reiterations during development, UNC‐86 operates in combination with distinct partner proteins to initiate and maintain terminal differentiation programs, by coregulating a vast array of functionally distinct identity determinants of specific neuron types. Mouse orthologs of unc‐86, the Brn3 genes, have been shown to fulfill a similar function in initiating and maintaining neuronal identity in specific parts of the mouse brain and similar functions appear to be carried out by the sole Drosophila ortholog, Acj6. The terminal selector function of UNC‐86 in many different neuron types provides a paradigm for neuronal identity regulation across phylogeny. This article is categorized under: Gene Expression and Transcriptional Hierarchies > Regulatory Mechanisms Invertebrate Organogenesis > Worms Nervous System Development > Vertebrates: Regional Development

DAF-16/FoxO and DAF-12/VDR control cellular plasticity both cell-autonomously and via interorgan signaling

“…To address the cell type and target specificity of the effects of DAF-16/FoxO and DAF-12/VDR, we considered a potential collaboration with terminal selector-type TFs, master regulatory TFs that initiate and maintain neuron type–specific gene expression programs during nervous system differentiation [ 64 ]. For example, DAF-16/FoxO-dependent up-regulation of a fosmid-based che-7 reporter in the BDU, NSM, or AIM neurons may be the result of daf-16 cooperating with the terminal selector of BDU, NSM, and AIM neuron identity, the unc-86 POU homeobox gene (which acts in distinct cofactor combinations in these different neuron types) [ 65 ]. To test this hypothesis, we asked whether the dauer-specific up-regulation of che-7 in BDU, NSM and AIM requires unc-86 .…”

The Prop1-like homeobox gene unc-42 specifies the identity of synaptically connected neurons

“…Many examples illustrate this regional bias in understanding gene function. For instance, the function of the mouse Brn3a POU homeobox gene has been extensively studied in some parts of the central nervous system, such as retinal ganglion cells, habenula, or peripheral sensory organs, but Brn3a function remains largely unexplored in other regions where the gene is expressed, including the interpeduncular nucleus or the superior colliculus (reviewed in Leyva-Díaz et al, 2020 ). Similarly, the function of the LIM homeobox Lhx2 has been well studied in some, but not other parts of the mouse central nervous system ( Chou and Tole, 2019 ).…”

Identification of retinal ganglion cell types and brain nuclei expressing the transcription factor Brn3c/Pou4f3 using a Cre recombinase knock‐in allele

“…We now describe Brn3c positive structures in the midbrain that include integration stations of sensory pathways, like the inferior colliculus, the intercollicular nucleus (Winer & Schreiner, 2005) and the deep layers of the SC as well as the mesencephalic trigeminal nucleus (containing proprioceptive neurons (Florez‐Paz, Bali, Kuner, & Gomis, 2016; Lipovsek et al, 2017)). Thus, Pou4f family members are repeatedly used in various stations of the sensory systems, offering an excellent example of evolutionary divergence of sensory circuits paralleled by expansions of transcription families dedicated to their specification (Hobert, 2011; Leyva‐Diaz, Masoudi, Serrano‐Saiz, Glenwinkel, & Hobert, 2020; Mao et al, 2016).…”

“…Brn3c is expressed in RGCs, nociceptors (Badea et al, 2012) and a subpopulation of proprioceptors (Oliver et al, 2020), and vestibulary and auditory hair cells (Xiang et al, 1997). We now describe Brn3c positive structures in the midbrain that include integration stations of sensory pathways, like the inferior colliculus, the intercollicular nucleus (Winer & Schreiner, 2005) (Hobert, 2011;Leyva-Diaz, Masoudi, Serrano-Saiz, Glenwinkel, & Hobert, 2020;Mao et al, 2016).…”