Mcidas mutant mice reveal a two-step process for the specification and differentiation of multiciliated cells in mammals
Mcidas mutant mice reveal a two-step process for the specification and differentiation of multiciliated cells in mammals
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DOI：
10.1242/dev.172643
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发表时间：
2019-03-01
期刊：
影响因子：
4.6
通讯作者：
Roy, Sudipto
中科院分区：
文献类型：
--
作者：
Lu, Hao;Anujan, Priyanka;Roy, Sudipto
多纤毛细胞（MCCs）上的运动纤毛在上皮细胞上的液体清除中起作用。对非洲爪蟾胚胎和患有先天性呼吸障碍的个体的研究减少了多运动纤毛（RGMC）的产生，涉及核蛋白MCIDAS（MCI）在MCC特化和分化的转录调节中。最近，一种旁系同源蛋白，包含双生子卷曲螺旋结构域（GMNC），也被证明是MCC形成所需的。令人惊讶的是，与目前持有的观点相反，我们发现Mci突变小鼠可以指定MCC前体。然而，这些前体不能产生多个基体，并成熟为单个纤毛细胞。我们确定了MCI在诱导多个基体的产生的后体途径组分中的重要作用。此外，GMNC和MCI与细胞周期调节因子E2F4和E2F5差异相关，这使它们能够激活不同的靶基因组（纤毛转录因子基因与基体扩增基因）。我们的数据建立了一个以前未被承认的两步模型MCC的发展：GMNC功能在MCC前体规格的初始步骤。GMNC诱导Mci表达，其驱动用于多细胞融合的基体产生的第二步。
Motile cilia on multiciliated cells (MCCs) function in fluid clearance over epithelia. Studies with Xenopus embryos and individuals with the congenital respiratory disorder reduced generation of multiple motile cilia (RGMC), have implicated the nuclear protein MCIDAS (MCI), in the transcriptional regulation of MCC specification and differentiation. Recently, a paralogous protein, geminin coiled-coil domain containing (GMNC), was also shown to be required for MCC formation. Surprisingly, in contrast to the presently held view, we find that Mci mutant mice can specify MCC precursors. However, these precursors cannot produce multiple basal bodies, and mature into single ciliated cells. We identify an essential role for MCI in inducing deuterosome pathway components for the production of multiple basal bodies. Moreover, GMNC and MCI associate differentially with the cell-cycle regulators E2F4 and E2F5, which enables them to activate distinct sets of target genes (ciliary transcription factor genes versus basal body amplification genes). Our data establish a previously unrecognized two-step model for MCC development: GMNC functions in the initial step for MCC precursor specification. GMNC induces Mci expression that drives the second step of basal body production for multiciliation.