Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Mol Cell Biol. 2011 Jul;31(14):2920-33. doi: 10.1128/MCB.05431-11. Epub 2011 May 23.
Cell polarity plays a critical role in the development of all metazoans; however, the mechanisms of cell polarity and the specific role of cell polarity pathways in mammalian organisms are still poorly understood. Lethal giant larvae (Lgl) is an apical-basal polarity gene identified in Drosophila, where it functions as a tumor suppressor controlling self-renewal and differentiation of progenitor cells. There are two orthologs of Lgl in mammalian genomes: Llgl1 and Llgl2. While mammalian Lgls are assumed to be tumor suppressor genes, little is known about their function in vivo. Here we report the functional analysis of murine Llgl2. We generated Llgl2(-/-) mice and found that Llgl2 functions as a polarity protein required for proper branching morphogenesis during placental development. Llgl2(-/-) pups are born as runts but quickly catch up in size and grow into normal-size adults. Surprisingly, no prominent phenotypes or spontaneous tumors were observed in adult Llgl2(-/-) mice. Analyses of placental trophoblasts reveal a critical role for Llgl2 in cell polarization and polarized cell invasion. We conclude that mammalian Llgl2 is required for proper polarized invasion of trophoblasts and efficient branching morphogenesis during placental development, but, unlike its Drosophila ortholog, it does not function as a canonical tumor suppressor gene.
细胞极性在所有后生动物的发育中起着关键作用；然而，细胞极性的机制以及细胞极性途径在哺乳动物中的特定作用仍知之甚少。致死性巨幼虫 (Lgl) 是在果蝇中鉴定的顶端-基底极性基因，在那里它作为一种肿瘤抑制因子，控制祖细胞的自我更新和分化。哺乳动物基因组中有两个 Lgl 的同源物：Llgl1 和 Llgl2。虽然哺乳动物 Lgls 被认为是肿瘤抑制基因，但它们在体内的功能知之甚少。在这里，我们报告了对鼠类 Llgl2 的功能分析。我们生成了 Llgl2(-/-) 小鼠，并发现 Llgl2 作为一种极性蛋白发挥作用，在胎盘发育过程中需要正确的分支形态发生。Llgl2(-/-) 幼仔出生时体型较小，但很快就会赶上正常体型并成长为正常体型的成年鼠。令人惊讶的是，成年 Llgl2(-/-) 小鼠没有观察到明显的表型或自发肿瘤。对胎盘滋养层细胞的分析揭示了 Llgl2 在细胞极化和极化细胞侵袭中的关键作用。我们得出结论，哺乳动物 Llgl2 是胎盘滋养层细胞正确极化侵袭和胎盘发育中有效分支形态发生所必需的，但与它的果蝇同源物不同，它不作为典型的肿瘤抑制基因发挥作用。
