Description

The genes encoding transcription factors that initiate the terminal differentiation programs within individual neurons have been termed “terminal selectors” (Hobert 2008).  They are considered master regulators of neuronal identity because they integrate upstream lineage inputs to ultimately drive (directly and/or indirectly) the expression of all terminal differentiation features of a neuron (Hobert 2008; Bertrand and Hobert 2010). The paired-like homeodomain transcription factor UNC-42 has been proposed to function as the terminal selector in the developmental specification of the ASH polymodal nociceptors in C. elegans (Baran et al. 1999). Consistent with the role of a terminal selector, unc-42(e419) loss-of-function mutants were shown to lack the expression of the putative chemoreceptor genes sra-6 and srb-6 specifically in the ASHs, while, for example, srb-6 expression in the ADL and ADF sensory neurons was unaffected (Baran et al. 1999). unc-42(e419) mutants also lack ASH expression of several other terminal identity markers: three Gα encoding genes (gpa-11, gpa-13 and gpa-15), the neuropeptide encoded by flp-21, and the eat-4 vesicular glutamate transporter (Serrano-Saiz et al. 2013).  Furthermore, loss of UNC-42 function disrupted behavioral responses to high osmolarity and nose touch (Baran et al. 1999), which are both detected primarily by the ASHs (Bargmann et al. 1990; Kaplan and Horvitz 1993).  However, the severity of the nose touch defect was likely due to developmental defects in both the ASH sensory neurons as well as some downstream interneurons, where altered glutamate receptor expression accompanies loss of UNC-42 (Baran et al. 1999; Brockie et al. 2001).

Table 1: Summary of the effect of unc-42(gk598) on ASH terminal marker gene expression
*sra-6 expression in ASH was previously reported to be affected by unc-42(e419) (Baran et al. 1999).

Using the unc-42(gk598) allele, we confirmed the role of UNC-42 in regulating ASH terminal markers, and identified seven additional genes whose ASH expression strongly depends upon UNC-42 (Figure 1 and Table 1).  These genes encode OSM-10, additional predicted GPCRs, transcription factors and a neuropeptide.  However, UNC-42 is unlikely to function as the sole terminal selector in ASH.  For example, srd-10 expression is only partially affected in the unc-42(gk598) mutants, with only ~20% of animals losing expression in one ASH (image not shown).  In addition, ASH expression of some genes (srz-1, nhr-79, nlp-3, osm-9, ocr-2, unc-40 and sax-3) was found to be unaffected in unc-42(gk598) animals (Table 1).  We note that several of these are either expressed broadly throughout the nervous system, or function in several sensory neurons.  As such, they may not necessarily be constituents of the terminally differentiated gene battery of the ASHs.  Combined, UNC-42 broadly regulates the expression of ASH identity markers, although additional transcription factors are likely to also contribute.