By the adult stage, UNC-40::GFP again becomes diffusely distributed. URA motor neurons. In conclusion, transcription factors operate as terminal selectors in distinct combinations in different neuron types, defining neuron type-specific identity features. Keywords:Caenorhabditis elegans, Homeobox, Neuron differentiation == INTRODUCTION == The development of the nervous system is a multistep process that employs a series of sequentially acting regulatory factors that successively restrict and determine cellular fates. During the process of terminal differentiation, individual neuron types acquire specific, hard-wired features that are maintained by the neuron type throughout the life of the animal. A number of transcription factors have been identified that initiate and maintain specific terminal differentiation programs in the developing nervous system (Hobert, 2011). For example, in mouse, the Nurr1 (Nr4a2) transcription factor initiates and maintains the terminal differentiation program of dopaminergic neurons in the midbrain (Smidt and Burbach, 2009), whereas NVP-BSK805 dihydrochloride the Pet1 transcription factor initiates and maintains the terminal differentiation program of serotonergic neurons (Liu et al., 2010). However, few neuronal transcription factors are expressed exclusively in only one specific neuronal cell type (Gray et al., 2004;Lein et al., 2007). For example, in addition to being expressed in midbrain dopaminergic NVP-BSK805 dihydrochloride neurons, Nurr1 is expressed in other non-dopaminergic neuronal cell types in Snr1 which its function is not well understood, such as the adult olfactory bulb, specific cortical areas and the hippocampus (Zetterstrm et al., 1996). The expression of a given transcription factor in distinct neuronal populations poses the fundamental question of whether there are underlying common themes in the activity of the transcription factor in distinct neuronal cell types. We have undertaken a systematic, in-depth comparison of the activity of two transcription factors in the development of several distinct neuronal cell types in the nematodeC. elegans, examining whether there are indeed conceptual similarities in the activities of a given transcription factor in distinct neuron types. We used, as a starting point, a member of the LIM homeobox gene family, an ancient family of neuronal patterning genes that display complex expression patterns in the nervous system of many different species, from invertebrates to vertebrates (Hobert and Westphal, 2000;Simmons et al., 2012;Srivastava et al., 2010). One unifying theme is their expression in terminally differentiating neurons (Hobert and Ruvkun, 1998;Moreno et al., 2005). We focus here on thettx-3LIM homeobox gene, which is the soleC. elegansmember of the Lhx2/9 subclass of LIM homeobox genes. In vertebrates, Lhx2 is expressed in multiple neuronal cell types and is required for the differentiation of olfactory sensory neurons (Hirota and Mombaerts, 2004;Kolterud et al., 2004), the specification of cortical neuron fate (Mangale et al., 2008) and the differentiation of thalamic neurons (Peukert et al., 2011). Whether there is a common theme in the function of Lhx2 in these distinct neuronal cell types is not known. TheC. elegansLhx2/9 orthologttx-3is exclusively expressed in a small number of neurons in distinct head ganglia (Altun-Gultekin et al., 2001).ttx-3null animals display broad differentiation defects in the cholinergic AIY interneuron class. AIY interneurons ofttx-3null mutants are generated and still express pan-neuronal features, but fail to express scores of terminal identity markers that define the functional properties of AIY, including genes required to synthesize and package acetylcholine, genes encoding neuropeptide receptors, various types of ion channels and many others (Altun-Gultekin et al., 2001;Hobert et al., 1997;Wenick and Hobert, 2004). TTX-3 exerts this control through direct binding to acis-regulatory motif shared by all of its target genes.ttx-3expression is turned on in the neuroblast that generates AIY and its expression is maintained throughout the life of the neuron through an autoregulatory feedback loop (Bertrand and Hobert, 2009) to ensure persistent expression of its target genes. A number of transcription factors have been described in theC. elegansnervous system that display similar broad-ranging effects on the terminal differentiation programs executed by the neurons in which they are expressed. These transcription factors have been called terminal selectors (Hobert, 2008;Hobert, 2011). It is still an open question how broadly the terminal selector concept applies throughout the nervous system; that is, how common it is that many distinct and functionally unrelated identity features of a specific neuron type are directly co-regulated by a transcription factor or a combination of NVP-BSK805 dihydrochloride transcription factors. Here, we investigate the role ofttx-3in.