Fig. 4: DDX-23-driven formation of MAB-10 (NAB) nuclear foci might control terminal differentiation and the onset of adulthood by transcriptionally repressing LIN-29 (EGR) target hedgehog and larval-specific genes.
From: A DEAD-box helicase drives the partitioning of a pro-differentiation NAB protein into nuclear foci
a Representative confocal fluorescent images of five animals expressing n5908[lin-29::gfp] (green channel), which fluorescently tags lin-29 at its endogenous locus, and nEx3004[MAB-10::mCherry] (red channel). Inset: Hypodermal seam cell nuclei. Scale bar, 40 μm. b DIC and confocal fluorescent images of hypodermal cells in 1-day-old wild-type, mab-10(tm2497), ddx-23(n5705) and mab-10(tm2497); ddx-23(n5705) adults expressing the reporter n5908[lin-29::gfp]. Images are representative of 5-8 animals per genotype. Scale bar, 40 μm. c RNA-Seq analysis of lin-29, mab-10, and ddx-23 mutant adults. The number of genes upregulated (black) and downregulated (gray) relative to wild-type adults are shown for the indicated genotypes. d Protein domain enrichment analysis of genes that are upregulated in lin-29, mab-10, and ddx-23 mutant adults, as identified by RNA-Seq analysis. Statistical tests were performed according to DAVID functional annotation tools76,77, where Fisher’s exact test was used to determine P values and false discovery rates were calculated by the Benjamini–Hochberg procedure to correct for multiple testing. e A proposed model for how DDX-23-driven formation of MAB-10 nuclear foci controls LIN-29/MAB-10 co-regulated target gene repression in the adult hypoderm. DDX-23 binds to and enhances the partitioning of MAB-10 proteins into repressive foci, causing silencing of LIN-29/MAB-10 co-repressed target genes—including larval-specific and Hedgehog-related genes—and thereby defining adult cell identity (left panel). Loss-of-function mutations in ddx-23 reduce MAB-10 partitioning into LIN-29 repressive foci and upregulate LIN-29/MAB-10 co-repressed genes including larval-specific and Hedgehog-related genes, resulting in a failure to maintain adult cell identity (right panel). Color key for proteins are as follows: DDX-23 (purple), MAB-10 (blue), LIN-29 (red), chromatin factor (yellow). f Models for how the heterochronic pathway regulates cell differentiation and the juvenile-to-adult transition in C. elegans (upper panel) and mammals (lower panel). For example, LIN28 signaling in mammals (LIN-28 signaling in C. elegans) coordinates the expression of EGR (C. elegans LIN-29) and NAB (C. elegans MAB-10) proteins, both let-7 microRNA-dependently via TRIM71 (mammalian homolog of the C. elegans LIN-41) and let-7-independently via IKAROS (mammalian homolog of the C. elegans HBL-1) and GFI1. The formation of nuclear foci that contain NAB (MAB-10) proteins is facilitated by a DEAD-box helicase protein (DDX-23) and function to transcriptionally repress EGR (LIN-29) target genes including proliferation-related genes and hedgehog-related genes. The repression of proliferation-related genes leads to cellular differentiation, while Hedgehog signaling leads to luteinizing hormone LHβ expression and the onset of puberty. DDX-23 was previously described to play a role in the primary microRNA processing of let-7 microRNA28 (dotted lines), possibly providing a feedback regulatory loop in this pathway. Source data for (c) is provided as a Source Data file.
