Caenorhabditis elegans PTR/PTCHD PTR-18 promotes the clearance of extracellular hedgehog-related protein via endocytosis

Autoři: Hirohisa Chiyoda aff001;  Masahiko Kume aff001;  Carla Cadena del Castillo aff002;  Kenji Kontani aff001;  Anne Spang aff002;  Toshiaki Katada aff001;  Masamitsu Fukuyama aff001
Působiště autorů: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan aff001;  Biozentrum, University of Basel, Basel, Switzerland aff002
Vyšlo v časopise: Caenorhabditis elegans PTR/PTCHD PTR-18 promotes the clearance of extracellular hedgehog-related protein via endocytosis. PLoS Genet 17(4): e1009457. doi:10.1371/journal.pgen.1009457
Kategorie: Research Article
doi: 10.1371/journal.pgen.1009457


Spatiotemporal restriction of signaling plays a critical role in animal development and tissue homeostasis. All stem and progenitor cells in newly hatched C. elegans larvae are quiescent and capable of suspending their development until sufficient food is supplied. Here, we show that ptr-18, which encodes the evolutionarily conserved patched-related (PTR)/patched domain-containing (PTCHD) protein, temporally restricts the availability of extracellular hedgehog-related protein to establish the capacity of progenitor cells to maintain quiescence. We found that neural progenitor cells exit from quiescence in ptr-18 mutant larvae even when hatched under starved conditions. This unwanted reactivation depended on the activity of a specific set of hedgehog-related grl genes including grl-7. Unexpectedly, neither PTR-18 nor GRL-7 were expressed in newly hatched wild-type larvae. Instead, at the late embryonic stage, both PTR-18 and GRL-7 proteins were first localized around the apical membrane of hypodermal and neural progenitor cells and subsequently targeted for lysosomal degradation before hatching. Loss of ptr-18 caused a significant delay in GRL-7 clearance, causing this protein to be retained in the extracellular space in newly hatched ptr-18 mutant larvae. Furthermore, the putative transporter activity of PTR-18 was shown to be required for the appropriate function of the protein. These findings not only uncover a previously undescribed role of PTR/PTCHD in the clearance of extracellular hedgehog-related proteins via endocytosis-mediated degradation but also illustrate that failure to temporally restrict intercellular signaling during embryogenesis can subsequently compromise post-embryonic progenitor cell function.

Klíčová slova:

Caenorhabditis elegans – Embryos – Hedgehog signaling – Larvae – Lysosomes – Molting – Reporter genes – Stem cells


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