Alternative splicing controls pan-neuronal homeobox gene expression

The pan-neuronally expressed and phylogenetically conserved CUT homeobox gene ceh-44/CUX orchestrates pan-neuronal gene expression throughout the nervous system of C. elegans. As in many other species, including humans, ceh-44/CUX is encoded by a complex locus that also codes for a Golgi-localized protein. How gene expression from this complex locus is controlled and, in C. elegans , directed to all cells of the nervous system has not been investigated. We show here that pan-neuronal expression of CEH-44/CUX is controlled by a pan-neuronal RNA splicing factor, UNC-75/CELF, the C. elegans homolog of vertebrate CELF proteins. UNC-75/CELF temporally and spatially specifies the production of an alternative, CEH-44/CUX homeobox gene-encoding transcript from a ubiquitously expressed gene locus, which also produces a Golgi apparatus-localized golgin protein, CONE-1 (“ C ASP o f ne matodes”). During embryogenesis the cone-1/ceh-44 locus exclusively produces the Golgi-localized CONE-1/CASP protein in all tissues, but upon the onset of postmitotic terminal differentiation of neurons, UNC-75/CELF induces the production of the alternative CEH-44/CUX CUT homeobox gene-encoding transcript, exclusively in the nervous system. Hence, UNC-75/CELF-mediated alternative splicing not only directs pan-neuronal gene expression, but also excludes a phylogenetically deeply conserved golgin from the nervous system, paralleling surprising spatial specificities of another golgin that we describe here as well. In summary, our findings provide novel insights into how all cells in a nervous system acquire pan-neuronal identity features.