Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
Biozentrum, University of Basel, Basel, Switzerland.
PLoS Genet. 2021 Apr 19;17(4):e1009457. doi: 10.1371/journal.pgen.1009457. eCollection 2021 Apr.
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.
信号的时空限制在动物发育和组织稳态中起着关键作用。新孵化的秀丽隐杆线虫幼虫中的所有干细胞和祖细胞都处于静止状态，可以暂停其发育，直到有足够的食物供应。在这里，我们表明，ptr-18 编码进化上保守的 patched-related（PTR）/patched 结构域包含（PTCHD）蛋白，它在时间上限制了细胞外 hedgehog 相关蛋白的可用性，从而建立了祖细胞维持静止的能力。我们发现，即使在饥饿条件下孵化，ptr-18 突变体幼虫中的神经祖细胞也会从静止中退出。这种不必要的再激活依赖于一组特定的 hedgehog 相关 grl 基因的活性，包括 grl-7。出乎意料的是，新孵化的野生型幼虫中既没有 PTR-18 也没有 GRL-7 表达。相反，在胚胎晚期，PTR-18 和 GRL-7 蛋白首先在真皮和神经祖细胞的顶膜周围定位，然后在孵化前被靶向溶酶体降解。ptr-18 的缺失导致 GRL-7 清除的显著延迟，导致这种蛋白质在新孵化的 ptr-18 突变体幼虫的细胞外空间中被保留。此外，PTR-18 的假定转运蛋白活性对于该蛋白的适当功能是必需的。这些发现不仅揭示了 PTR/PTCHD 在通过内吞作用介导的降解清除细胞外 hedgehog 相关蛋白中的先前未描述的作用，而且还表明在胚胎发生期间未能时空限制细胞间信号会随后损害胚胎后的祖细胞功能。
