Mazahery Ahmad Reza, Suzuki Kentaro, Nagafuchi Akira, Miyajima Masayasu, Nakagata Naomi, Orvis Grant D, Behringer Richard R, Yamada Gen
Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan.
Congenit Anom (Kyoto). 2013 Mar;53(1):34-41. doi: 10.1111/cga.12001.
β-catenin is a molecule belonging to the armadillo family of proteins that is a crucial core-component of cellular adherens junctions, and a component of the canonical Wnt-signaling pathway. We attempted to analyze the functional significance of ectodermal-derived β-catenin during the development of the mouse genital tubercle, a mammalian anlage of the external genitalia. For this purpose, the conditional loss of function mouse mutant Wnt7a-Cre;β-cat(f/f) was utilized. Loss of ectodermal β-catenin leads to the formation of urethral cleft during preputial uprising. Although expression of E-cadherin was retained in the genital tubercle ectoderm of mutants, probably through plakoglobin compensatory expression, expression of other crucial adherens junction components such as α-catenin and F-actin in the cell-cell border were distinctly reduced. We also showed that β-catenin is necessary for the expression of its transcriptional downstream target Lef-1 which was localized in the basal layer of the preputial ectoderm, excluding the midventral region at E15.5. Such specialized region was observed to possess cytoplasmic β-catenin expression at this stage. Coincidentally, mitotically active cells were also found in the basal layer of the preputial ectoderm excluding the midventral region. In mutant genital tubercle, cell proliferation in the preputial ectoderm was decreased. Taken together, we suggest that ectodermal β-catenin is necessary not only to maintain adherens junction integrity, but also to regulate cell proliferation possibly through Lef-1 functions. Thus, β-catenin is shown to perform dual functions, initially as an adhesion molecule and later on as a possible transcription factor.
β-连环蛋白是一种属于犰狳蛋白家族的分子，它是细胞黏附连接的关键核心成分，也是经典Wnt信号通路的组成部分。我们试图分析外胚层来源的β-连环蛋白在小鼠生殖结节（外生殖器的哺乳动物原基）发育过程中的功能意义。为此，我们利用了条件性功能丧失小鼠突变体Wnt7a-Cre;β-cat(f/f)。外胚层β-连环蛋白的缺失会导致包皮隆起过程中尿道裂的形成。尽管E-钙黏蛋白在突变体的生殖结节外胚层中仍有表达，可能是通过桥粒芯蛋白的代偿性表达，但细胞间边界处其他关键黏附连接成分如α-连环蛋白和F-肌动蛋白的表达明显减少。我们还表明，β-连环蛋白对于其转录下游靶点Lef-1的表达是必需的，Lef-1定位于E15.5时包皮外胚层的基底层，但不包括腹中部区域。在这个阶段，观察到这样的特殊区域具有细胞质β-连环蛋白表达。巧合的是，在不包括腹中部区域的包皮外胚层基底层中也发现了有丝分裂活跃的细胞。在突变的生殖结节中，包皮外胚层的细胞增殖减少。综上所述，我们认为外胚层β-连环蛋白不仅对于维持黏附连接的完整性是必需的，而且可能通过Lef-1的功能来调节细胞增殖。因此，β-连环蛋白显示出双重功能，最初作为一种黏附分子，后来可能作为一种转录因子。
