A bHLH Code for Sexually Dimorphic Form and Function of the C. elegans Somatic Gonad

Abstract

Summary How sexually dimorphic gonads are generated is a fundamental question at the interface of developmental and evolutionary biology [1–3]. In C. elegans, sexual dimorphism in gonad form and function largely originates in different apportionment of roles to three “regulatory cells” of the somatic gonad primordium in young larvae. Their essential roles include leading gonad arm outgrowth, serving as the germline niche, connecting to epithelial openings, and organizing reproductive organ development. The development and function of the regulatory cells in both sexes requires the basic Helix-Loop-Helix (bHLH) transcription factor HLH-2, the sole ortholog of the E proteins mammalian E2A and Drosophila Daughterless [4–8], yet how they adopt different fates to execute their different roles has been unknown. Here, we show that each regulatory cell expresses a distinct complement of bHLH-encoding genes--and therefore distinct HLH-2:bHLH dimers--and formulate a “bHLH code” hypothesis for regulatory cell identity. We support this hypothesis by showing that the bHLH gene complement is both necessary and sufficient to confer particular regulatory cell fates. Strikingly, prospective regulatory cells can be directly reprogrammed into other regulatory cell types simply by loss or ectopic expression of bHLH genes, and male-to-female and female-to-male transformations indicate that the code is instructive for sexual dimorphism. The “bHLH code” appears to be embedded in a bow-tie regulatory architecture [9,10], wherein sexual, positional, temporal, and lineage inputs connect through bHLH genes to diverse outputs for terminal features, and provides a plausible mechanism for the evolutionary plasticity of gonad form seen in nematodes [11–15].

Sexual dimorphism of niche architecture and regulation of theCaenorhabditis elegansgermline stem cell pool

“…, 2014). The arg-1 promoter, by contrast, gives a strong signal in mDTCs, but no signal in hDTCs (this paper; Sallee, Littleford, et al. , 2017).…”

A tissue-specific enhancer of the C. elegans nhr-67/tailless gene drives coordinated expression in uterine stem cells and the differentiated anchor cell

“…A genome-wide approach for identifying candidate bHLH binding sites in C. elegans identified these sequences as candidate targets for HLH-2 heterodimers with 9 candidate HLH partners (HLH-3, −4, −10, −14, −15, −19, HND-1 and LIN-32) (Grove et al, 2009). Directed studies on the binding of HLH-2 have demonstrated that this sequence will also bind HLH-2 homodimers both in vivo and in vitro (Krause et al, 1997; Harfe et al, 1998; Sallee and Greenwald, 2015, Sallee et al, 2017).…”

Integration of EGFR and LIN-12/Notch Signaling by LIN-1/Elk1, the Cdk8 Kinase Module, and SUR-2/Med23 in Vulval Precursor Cell Fate Patterning in Caenorhabditis elegans

“…We assayed the effect of the CKM using null alleles for cdk-8 and cic-1 on the expression of the lag-2 transcriptional reporter arIs222[lag-2p::tagrfp], which contains 7.2 kb of 59 flanking region (Sallee and Greenwald 2015;Sallee et al, 2017). This reporter is strongly expressed in P6.p and its descendants in otherwise wild-type worms ( Figure 1B), and is expressed normally in mutants lacking the CKM components cdk-8 or cic-1 ( Figure 1C).…”