PBX1 acts as terminal selector for olfactory bulb dopaminergic neurons

Abstract

Neuronal specification is a protracted process that begins with the commitment of progenitor cells and culminates with the generation of mature neurons. Many transcription factors are continuously expressed during this process, but it is presently unclear how these factors modify their targets as cells transition through different stages of specification. In olfactory bulb adult neurogenesis, the transcription factor PBX1 controls neurogenesis in progenitor cells and survival of migrating neuroblasts. Here we show that, at later differentiation stages, PBX1 also acts as a terminal selector for the dopaminergic fate. PBX1 is additionally required for the morphological maturation of dopaminergic neurons and to repress alternative interneuron fates, findings that expand the known repertoire of terminal-selector actions. Finally, we reveal that the temporal diversification of PBX1 functions in neuronal specification is achieved, at least in part, through the dynamic regulation of alternative splicing. In C. elegans, PBX/CEH-20 also acts as dopaminergic terminal selector what suggests an ancient role for PBX factors in the regulation of dopaminergic terminal differentiation.

Joint actions of diverse transcription factor families establish neuron-type identities and promote enhancer selectivity

“…Mouse orthologs for ast-1, ceh-43 and ceh-20 (Etv1, Dlx2 and Pbx1 respectively) are required for mouse olfactory bulb dopaminergic terminal differentiation, thus the dopaminergic terminal differentiation program seems to be phylogenetically conserved (Brill et al, 2008; Cave et al, 2010; Flames and Hobert, 2009; Remesal et al, 2020). Remarkably, Meis2, the mouse ortholog of unc-62 , Pax6, the mouse ortholog of vab-3 and Nr2f1, the mouse ortholog of unc-55 are also necessary for olfactory bulb dopaminergic specification (Agoston et al, 2014; Bovetti et al, 2013; Brill et al, 2008).…”

“…Mouse TF orthologs of the C. elegans dopaminergic terminal regulatory program are also required for olfactory bulb dopaminergic terminal specification, which is the most ancestral dopaminergic population of the mammalian brain (Agoston et al 2014; Brill et al 2008; Flames and Hobert 2009; Bovetti et al 2013; Remesal et al 2020; Qiu et al 1995). Here we find mouse TFs can, in most cases, functionally substitute their worm orthologs suggesting both dopaminergic neuronal populations share deep homology, which refers to the relationship between cells in distant species that share their genetic regulatory programs (Shubin et al 2009).…”

“…We focused mainly on MA neurons not only because they are evolutionary conserved and clinically relevant in humans (Flames and Hobert 2011), but also because the MA superclass comprises a set of neuronal types with very diverse developmental origins and functions in both worms and humans (Flames and Hobert 2011). Importantly, we have previously shown that gene regulatory networks directing the terminal fate of two types of MA neurons (dopaminergic and serotonergic neurons) are conserved in worms and mammals (Lloret-Fernández et al 2018; Doitsidou et al 2013; Flames and Hobert 2009; Remesal et al 2020). Thus, the identification of common principles underlying MA specification could help unravel general rules for neuron-type specification.…”

The transcription factor LAG-1/CSL plays a Notch-independent role in controlling terminal differentiation, fate maintenance, and plasticity of serotonergic chemosensory neurons

“…Altogether, LAG-1 shows all known attributes for a terminal selector: cell fate induction, direct action on effector genes, and cell fate maintenance [8]. In addition to activating roles for terminal selectors, in some contexts, these TFs have been shown to also act as repressors of alternative cell fates [44][45][46]; although our work has not deeply explored this possibility for LAG-1, lag-1 mutants do not up-regulate expression of odr-1 reporter in the ADF neuron (odr-1 is an effector gene for AWB, the sister cell of ADF), suggesting that lag-1 acts mainly activating gene expression rather than repressing alternative fates.…”

DamID identifies targets of CEH-60/PBX that are associated with neuron development and muscle structure in Caenorhabditis elegans

“…Because CEH-60 does not appear to influence butanone sensing, we maintain that the method through which CEH-60 alters fat mobilization and storage, is through its documented regulation of vitellogenesis. Future work may yet unveil CEH-60's cryptic role or function in olfactory AWC neurons, further motivated by (1) the recent discovery that PBX1, coding for ceh-60's homolog in vertebrates, acts as a terminal selector for olfactory bulb neuron differentiation in mice [79], and (2) the knowledge that in C. elegans, olfactory learning depends on the odor-sensing (ceh-60expressing) AWC neurons but also involves signaling from DBL-1/TGF-β [80], which is here identified as a putative gene target for CEH-60 (S1 Table). DBL-1 could indeed be the signaling…”