daf-4

Two genes, sma-11 and sma-20, also influence regulation of the developmentally arrested dauer larval stage, suggesting a role in a second characterized TGFbeta pathway in C. elegans.

The activity may be an evolutionary remnant, owing to daf-1's origin near the type I/type II divergence, or it may be an innovation that evolved in nematodes. daf-1 and daf-4 promoters both mediated expression of green fluorescent protein in the nervous system, indicating that a DAF-1/DAF-4 receptor complex may activate a neuronal signaling pathway.

Mutations in daf-4, sma-2, sma-3, and sma-4, which disrupt TGFbeta-like signaling, result in aberrant migrations and morphologically abnormal spicules. daf-4, and hence the TGFbeta-like signal, is required prior to or during cell migrations.

Mutations in sma-6 generate the reduced body size (Sma) and abnormal mail tail (Mab) phenotypes identical to those observed in daf-4 and sma-2, sma-3, sma-4 mutants (C. elegans Smads), indicating that they function in a common signaling pathway.

Target prediction and pathway enrichment analyses showed daf-4, daf-1, fos-1, cmk-1, and unc-30 to be potential effectors of nicotine addiction.

As TSP-12 and TSP-14 are conserved in mammals, our findings suggest that the mammalian TSP-12 and TSP-14 homologs may also function in regulating transmembrane protein recycling and BMP signaling.

In intestine, SER-5, DAF-2, EGL-15, and GON-2 mediated "sword effect" and FSHR-1 mediated "shield effect" in response to the primordial response of the 6-PPDQ-induced reproductive toxicity.

The epidermal cell-surface receptors (DCAR-1 and DAF-4) mainly mediated the primordial response by enhancing epidermal innate immune response or reproductive aging, and the intestinal cell-surface receptors (SER-5, FSHR-1, GON-2, DAF-2, and EGL-15) mainly mediated the primordial response by inducing oxidative stress or intestinal innate immune response.

We describe a novel role of this pathway in maintaining receptor gene expression in the adult and show that the DAF-4 type II TGF-beta receptor functions cell-autonomously to modulate chemoreceptor expression.

Our study demonstrates the intersection between the autophagy pathway and the endocytic pathway, providing insights into the pathogenesis of amyotrophic lateral sclerosis (ALS) and Vici syndrome.Abbreviations: ALM: anterior lateral microtubule; ATG: autophagy related; AVM: anterior ventral microtubule; CORVET: class C core vacuole/endosome tethering; DAF-4: abnormal dauer formation 4; DIC: differential interference contrast; EPG: ectopic PGL granules; EPG-5: ectopic P granules 5; GAP: GTPase activating protein; GFP: green fluorescent protein; HOPS: homotypic fusion and vacuole protein sorting; H.s.IL2RA/hTAC: human interleukin 2 receptor subunit alpha; H.s.TFR/hTfR: human transferrin receptor; L1/L4: the first/fourth larval; mCh: mCherry; MIG-14: abnormal cell migration 14; PLM: posterior lateral microtubule; PVM: posterior ventral microtubule; RAB: ras-related protein; RFP: red fluorescent protein; RME-1: receptor mediated endocytosis 1; SMA-6: small 6; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SNX: sorting nexin; TBC-2: TBC1 (Tre-2/Bub2/Cdc16) domain family 2; TGFB/TGF-β: transforming growth factor beta; TGN: trans-Golgi network; VPS: related to yeast vacuolar protein sorting factor; WT: wild type.

They also raise the possibility of an unexpected function for DAF-1 and DAF-8 that is independent of their normal upstream activator, DAF-7.

The activity may be an evolutionary remnant, owing to daf-1's origin near the type I/type II divergence, or it may be an innovation that evolved in nematodes. daf-1 and daf-4 promoters both mediated expression of green fluorescent protein in the nervous system, indicating that a DAF-1/DAF-4 receptor complex may activate a neuronal signaling pathway.

We have cloned and characterized lon-1, a gene with homology to the cysteine-rich secretory protein (CRISP) family of proteins. lon-1 regulates body size morphogenesis, but does not affect male tail development. lon-1 is expressed in hypodermal tissues, which is the focus of body size determination, similar to sma-2, sma-4, and sma-6.

Using genetic methods, we show that lon-1 lies downstream of the Sma/Mab signaling cascade and demonstrate that lon-1 mRNA levels are up-regulated in sma-6-null mutant animals.

Mutations in daf-4, sma-2, sma-3, and sma-4, which disrupt TGFbeta-like signaling, result in aberrant migrations and morphologically abnormal spicules. daf-4, and hence the TGFbeta-like signal, is required prior to or during cell migrations.

In epg-5 mutants, SMA-6 and MIG-14 are trapped within hybrid endosomal structures, which colocalize with SNX-1- and SNX-3-labeled vesicles, respectively.

Thus, NIMA family kinases carry out multiple functions during endocytosis in both worms and humans, consistent with our previous observation that human NEKL-3 orthologs can rescue molting and trafficking defects in C. elegans nekl-3 mutants.

Four of these 11 genes, sma-9, sma-14, sma-16, and sma-20 affect male tail morphogenesis as well as body size.

Our study demonstrates the intersection between the autophagy pathway and the endocytic pathway, providing insights into the pathogenesis of amyotrophic lateral sclerosis (ALS) and Vici syndrome.Abbreviations: ALM: anterior lateral microtubule; ATG: autophagy related; AVM: anterior ventral microtubule; CORVET: class C core vacuole/endosome tethering; DAF-4: abnormal dauer formation 4; DIC: differential interference contrast; EPG: ectopic PGL granules; EPG-5: ectopic P granules 5; GAP: GTPase activating protein; GFP: green fluorescent protein; HOPS: homotypic fusion and vacuole protein sorting; H.s.IL2RA/hTAC: human interleukin 2 receptor subunit alpha; H.s.TFR/hTfR: human transferrin receptor; L1/L4: the first/fourth larval; mCh: mCherry; MIG-14: abnormal cell migration 14; PLM: posterior lateral microtubule; PVM: posterior ventral microtubule; RAB: ras-related protein; RFP: red fluorescent protein; RME-1: receptor mediated endocytosis 1; SMA-6: small 6; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SNX: sorting nexin; TBC-2: TBC1 (Tre-2/Bub2/Cdc16) domain family 2; TGFB/TGF-β: transforming growth factor beta; TGN: trans-Golgi network; VPS: related to yeast vacuolar protein sorting factor; WT: wild type.

In addition, defects were observed in the uptake of clathrin-dependent (SMA-6/Type I BMP receptor) and independent cargoes (DAF-4/Type II BMP receptor) from the basolateral surface of epidermal cells after NEKL-2 or NEKL-3 depletion.