Here we show that in the nematode Caenorhabditis elegans mutational inactivation of two autophagy genes unc-51/atg1 and bec-1/atg6/beclin1 results in small body size without affecting cell number. Furthermore, loss-of-function mutations in unc-51 and bec-1 suppress the giant phenotype of mutant animals with aberrant insulin-like growth factor-1 (insulin/IGF-1) or transforming growth factor-b (TGF-b) signaling. This function for unc-51 and bec-1 in cell size control and their interaction with these two growth modulatory pathways may represent a link between the hormonal and nutritional regulation of cell growth.
The vulva of the Caenorhabditis elegans hermaphrodite develops from a subset of six vulval precursor cells (VPCs) by the combined effect of the Ras, Wingless and Notch signaling cascades, and of three redundant synMuv (synthetic Multivulva) pathways grouped into classes A, B and C. Here we show that signaling via the GLI- (Glioma-associated protein) like transcription factor TRA-1, which is the terminal regulator of the C. elegans sex determination cascade, is a newly discovered pathway specifying vulval cell fates. We found that TRA-1 accumulates in, and regulates the fusion process of, cells (including the VPCs and hypodermal cells) involved in vulval patterning. TRA-1 also influenced the expression of the Hox gene lin-39, a central regulator of vulval development. Furthermore, inactivation of tra-1, which transforms animals with hermaphrodite-specific karyotype into males, promoted vulval induction in synMuv A, but not in synMuv B, mutant background. This implies that TRA-1 interacts with the class B synMuv genes, many of which are involved in chromatin-mediated transcriptional repression of cell proliferation. These results may help to understand how compromised GLI activity in humans leads to cancer. Together, we suggest that the GLI protein family involved in several key developmental processes in both invertebrates and vertebrates regulates somatic cell fates through influencing, at least in part, the expression of specific Hox genes.
BackgroundHox genes play a central role in axial patterning during animal development. They are clustered in the genome and specify cell fate in sequential domains along the anteroposterior (A-P) body axis in a conserved order that is co-linear with their relative genomic position. In the soil worm Caenorhabditis elegans, this striking rule of co-linearity is broken by the anterior Hox gene ceh-13, which is located between the two middle Hox paralogs, lin-39 and mab-5, within the loosely organized nematode Hox cluster. Despite its evolutionary and developmental significance, the functional consequence of this unusual genomic organization remains unresolved.ResultsIn this study we have investigated the role of ceh-13 in different developmental processes, and found that its expression and function are not restricted to the anterior body part. We show that ceh-13 affects cell migration and fusion as well as tissue patterning in the middle and posterior body regions too. These data reveal novel roles for ceh-13 in developmental processes known to be under the control of middle Hox paralogs. Consistently, enhanced activity of lin-39 and mab-5 can suppress developmental arrest and morphologic malformation in ceh-13 deficient animals.ConclusionOur findings presented here show that, unlike other Hox genes in C. elegans which display region-specific accumulation and function along the A-P axis, the expression and functional domain of the anterior Hox paralog ceh-13 extends beyond the anterior region of the worm. Furthermore, ceh-13 and the middle Hox paralogs share several developmental functions. Together, these results suggest the emergence of the middle-group Hox genes from a ceh-13-like primordial Hox ancestor.
A c c e p t e d M a n u s c r i p t Billes et al., 2018., Revision 3 Autophagy in eye development 3 microtubule-associated protein 1 light chain 3; MF, morphogenetic furrow; PE, Tables (S1, S2), and Suppl.
Figures and Figure Legends (S1 to S31).A c c e p t e d M a n u s c r i p t
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