An unusual Zn-finger/FH2 domain protein controls a left/right asymmetric neuronal fate decision in C. elegans

Abstract

Gene regulatory networks that control the terminally differentiated state of a cell are, by and large, only superficially understood. In a mutant screen aimed at identifying regulators of gene batteries that define the differentiated state of two left/right asymmetric C. elegans gustatory neurons, ASEL and ASER, we have isolated a mutant, fozi-1, with a novel mixed-fate phenotype, characterized by de-repression of ASEL fate in ASER. fozi-1 codes for a protein that functions in the nucleus of ASER to inhibit the expression of the LIM homeobox gene lim-6, neuropeptide-encoding genes and putative chemoreceptors of the GCY gene family. The FOZI-1 protein displays a highly unusual domain architecture, that combines two functionally essential C2H2 zinc-finger domains, which are probably involved in transcriptional regulation, with a formin homology 2 (FH2) domain, normally found only in cytosolic regulators of the actin cytoskeleton. We demonstrate that the FH2 domain of FOZI-1 has lost its actin polymerization function but maintains its phylogenetically ancient ability to homodimerize. fozi-1 genetically interacts with several transcription factors and micro RNAs in the context of specific regulatory network motifs. These network motifs endow the system with properties that provide insights into how cells adopt their stable terminally differentiated states.

Two distinct types of neuronal asymmetries are controlled by the Caenorhabditis elegans zinc finger transcription factor die-1

“…fozi-1 is a zinc finger transcription factor expressed in the ASER neurons from threefold embryos throughout larval and adult stages (Supplemental Fig. S1; Johnston et al 2006). We found that in fozi-1 mutants, die-1 fosmid reporter expression becomes derepressed in the ASER neuron but only in later larval and adult stages (Fig.…”

“…3B,C). This is a double-negative feedback control mechanism, as die-1 also represses fozi-1 in ASEL (Johnston et al 2006).…”

Genetic Screens forCaenorhabditis elegansMutants Defective in Left/Right Asymmetric Neuronal Fate Specification

“…We describe here genetic screens for neuronal fate mutants in the nematode Caenorhabditis elegans that focus on a cell fate decision executed by a single neuron class, the ASE gustatory neurons. This neuron class is composed of two morphologically bilaterally symmetric neurons, ASE We have previously reported the identification of mutants that affect the development of the left/right asymmetry of the ASE neurons (Chang et al 2003; Hobert 2003, 2005;Johnston et al 2006). These mutants, which we termed lsy mutants (for laterally symmetric) to indicate their role in controlling the fate of two left/right asymmetric neurons, fell into four distinct classes ( Figure 1A).…”

“…We have previously reported the identification of mutants that affect the development of the left/right asymmetry of the ASE neurons (Chang et al 2003;Hobert 2003, 2005;Johnston et al 2006). These mutants, which we termed lsy mutants (for laterally symmetric) to indicate their role in controlling the fate of two left/right asymmetric neurons, fell into four distinct classes ( Figure 1A).…”

“…Previously published mutants (Chang et al 2003;Hobert 2003, 2005;Johnston et al 2006) were derived from relatively small-scale screens totaling $15,000 haploid genomes (Table 1). We describe here mutants from those previous screens that…”