Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Department of Molecular Biology, Princeton University, Princeton, NJ 08540, USA.
Development. 2019 May 15;146(10):dev168427. doi: 10.1242/dev.168427.
During embryonic gonad coalescence, primordial germ cells (PGCs) follow a carefully choreographed migratory route circumscribed by guidance signals towards somatic gonadal precursor cells (SGPs). In , SGP-derived Hedgehog (Hh), which serves as a guidance cue for the PGCs, is potentiated by mesodermally restricted HMGCoA-reductase (Hmgcr) and the ABC transporter Multi-drug-resistant-49 (Mdr49). Given the importance of cholesterol modification in the processing and long-distance transmission of the Hh ligand, we have analyzed the involvement of the Niemann-Pick disease type C-1a (NPC1a) protein, a cholesterol transporter, in germ cell migration and Hedgehog signaling. We show that mesoderm-specific inactivation of results in germ cell migration defects. Similar to , PGC migration defects in the embryos are ameliorated by a cholesterol-rich diet. Consistently, reduction in weakens the ability of ectopic HMG Coenzyme A reductase () to induce germ cell migration defects. Moreover, compromising levels influences Hh signaling adversely during wing development, a process that relies upon long-range Hh signaling. Last, doubly heterozygous embryos () display enhanced germ cell migration defects when compared with single mutants ( or ), supporting cooperative interaction between the two.
在胚胎性腺融合过程中，原始生殖细胞（PGC）沿着由指导信号限定的精心编排的迁移途径向体生殖前体细胞（SGP）迁移。在 中，SGP 衍生的 Hedgehog（Hh）作为 PGC 的指导线索，被中胚层受限的 HMGCoA 还原酶（Hmgcr）和 ABC 转运蛋白多药耐药蛋白 49（Mdr49）增强。鉴于胆固醇修饰在 Hh 配体的加工和长距离传递中的重要性，我们分析了尼曼-匹克病 C1 型（NPC1a）蛋白，一种胆固醇转运蛋白，在生殖细胞迁移和 Hedgehog 信号中的参与。我们表明，结果导致生殖细胞迁移缺陷。与 相似，富含胆固醇的饮食可改善 胚胎中 PGC 迁移缺陷。一致地，降低 削弱了异位 HMG Coenzyme A 还原酶（）诱导生殖细胞迁移缺陷的能力。此外，在翼发育过程中，降低 水平会对 Hh 信号产生不利影响，这一过程依赖于长距离 Hh 信号。最后，与单突变体（或）相比，双杂合子胚胎（）显示出增强的生殖细胞迁移缺陷，支持两者之间的合作相互作用。
