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PLoS One. 2011;6(11):e26811. doi: 10.1371/journal.pone.0026811. Epub 2011 Nov 1.

Multiple doublesex-related genes specify critical cell fates in a C. elegans male neural circuit.

Siehr MS, Koo PK, Sherlekar AL, Bian X, Bunkers MR, Miller RM, Portman DS, Lints R.

Source

Department of Biology, Texas A & M University, College Station, Texas, United States of America.

Abstract

BACKGROUND:

In most animal species, males and females exhibit differences in behavior and morphology that relate to their respective roles in reproduction. DM (Doublesex/MAB-3) domain transcription factors are phylogenetically conserved regulators of sexual development. They are thought to establish sexual traits by sex-specifically modifying the activity of general developmental programs. However, there are few examples where the details of these interactions are known, particularly in the nervous system.

METHODOLOGY/PRINCIPAL FINDINGS:

In this study, we show that two C. elegans DM domain genes, dmd-3 and mab-23, regulate sensory and muscle cell development in a male neural circuit required for mating. Using genetic approaches, we show that in the circuit sensory neurons, dmd-3 and mab-23 establish the correct pattern of dopaminergic (DA) and cholinergic (ACh) fate. We find that the ETS-domain transcription factor gene ast-1, a non-sex-specific, phylogenetically conserved activator of dopamine biosynthesis gene transcription, is broadly expressed in the circuit sensory neuron population. However, dmd-3 and mab-23 repress its activity in most cells, promoting ACh fate instead. A subset of neurons, preferentially exposed to a TGF-beta ligand, escape this repression because signal transduction pathway activity in these cells blocks dmd-3/mab-23 function, allowing DA fate to be established. Through optogenetic and pharmacological approaches, we show that the sensory and muscle cell characteristics controlled by dmd-3 and mab-23 are crucial for circuit function.

CONCLUSIONS/SIGNIFICANCE:

In the C. elegans male, DM domain genes dmd-3 and mab-23 regulate expression of cell sub-type characteristics that are critical for mating success. In particular, these factors limit the number of DA neurons in the male nervous system by sex-specifically regulating a phylogenetically conserved dopamine biosynthesis gene transcription factor. Homologous interactions between vertebrate counterparts could regulate sex differences in neuron sub-type populations in the brain.

PMID:: 22069471; [PubMed - indexed for MEDLINE]
PMCID:: PMC3206049

Free PMC Article

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Figure 2

Interactions between ast-1 and the DM domain genes regulate ray A-neuron neurotransmitter fates.

A, B. dmd-3 and ast-1 are expressed in the A-neurons of the rays. Fluorescent micrographs showing DMD-3::YFP (A) and AST-1::YFP (B) expression in A-neurons of adult male rays (ventral view, posterior to the right, 600× magnification). The DMD-3::YFP fusion protein lacks a nuclear localization signal, consequently the fusion protein fills the entire neuron. The AST-1::YFP fusion protein contains the entire coding sequence and so localizes predominantly to cell nuclei [70]. Both reporters are expressed in the A-neurons of all rays. The arrowhead indicates gut auto-fluorescence; the arrows indicate copulatory spicule (Sp) auto-fluorescence. C–H. Expression of dopaminergic (DA) and cholinergic (ACh) fate in adult males of the genotype shown (lateral view, dorsal up, posterior to the right, 600× magnification). Ray cells of the left and right side of the tail are located in the left and right lumbar ganglia, respectively (white dotted line). C–F. DA fate expression. DIC and fluorescent micrographs of the same animal are superimposed. C. Wild type (WT) and D. dmd-3(0) males showing DA fate expression, visualized with a pdat-1::GFP reporter transgene. E. ast-1(lf) male showing the absence of DA marker expression in ray neurons. Here, the marker is CAT-2::GFP as ast-1(lf) mutations do not significantly affect pdat-1::GFP expression (See Table S1). In wild type males, CAT-2::GFP is expressed in the spicule socket cells (SPso) as well as the DA neurons (data not shown). ast-1 mutations reduce, but do not eliminate SPso expression. F. ast-1(lf); dmd-3(0) male showing an absence of DA marker expression in all A-neurons (compare with D). G, H. ACh fate expression. Fluorescent images of UNC-17::GFP expression in the A-neurons of G. WT and H. dmd-3(0) males. Scale bar (10 µM) applies to all images.

Multiple doublesex-Related Genes Specify Critical Cell Fates in a C. elegans Male Neural Circuit

PLoS One. 2011;6(11):e26811.