Department of Human Genetics, University of Utah, Salt Lake City, Utah, USA.
Dev Dyn. 2022 Apr;251(4):625-644. doi: 10.1002/dvdy.422. Epub 2021 Sep 28.
Pax2 is required for optic fissure development in many organisms, including humans and zebrafish. Zebrafish loss-of-function mutations in pax2a display coloboma, yet the etiology of the morphogenetic defects is unclear. Further, pax2 is duplicated in zebrafish, and a role for pax2b in optic fissure development has not been examined.
Using a combination of imaging and molecular genetics, we interrogated a potential role for pax2b and examined how loss of pax2 affects optic fissure development. Although optic fissure formation appears normal in pax2 mutants, an endothelial-specific subset of periocular mesenchyme (POM) fails to initially localize within the optic fissure, yet both neural crest and endothelial-derived POM ectopically accumulate at later stages in pax2a and pax2a; pax2b mutants. Apoptosis is not up-regulated within the optic fissure in pax2 mutants, yet cell death is increased in tissues outside of the optic fissure, and when apoptosis is inhibited, coloboma is partially rescued. In contrast to pax2a, loss of pax2b does not appear to affect optic fissure morphogenesis.
Our results suggest that pax2a, but not pax2b, supports cell survival outside of the optic fissure and POM abundance within it to facilitate optic fissure closure.
在包括人类和斑马鱼在内的许多生物体中，Pax2 是视神经裂发育所必需的。斑马鱼 pax2a 基因的功能丧失突变会导致眼眶裂，但其形态发生缺陷的病因尚不清楚。此外，斑马鱼中 Pax2 基因被复制，而 pax2b 在视神经裂发育中的作用尚未被研究。
我们通过成像和分子遗传学的组合，研究了 pax2b 的潜在作用，并检查了 pax2 缺失如何影响视神经裂的发育。尽管 pax2 突变体中的视神经裂形成似乎正常，但眶周间充质（POM）的一个内皮特异性亚群最初未能定位于视神经裂内，而神经嵴和内皮衍生的 POM 在 pax2a 和 pax2a;pax2b 突变体中异位积聚。在 pax2 突变体中，视神经裂内没有上调细胞凋亡，但细胞死亡在视神经裂外的组织中增加，当抑制细胞凋亡时，眼眶裂部分得到挽救。与 pax2a 不同的是，pax2b 的缺失似乎不会影响视神经裂的形态发生。
我们的结果表明，pax2a 而不是 pax2b 支持视神经裂外的细胞存活和 POM 在视神经裂内的丰度，以促进视神经裂的闭合。
