Redundant functions of Rac GTPases in inner ear morphogenesis.
Redundant functions of Rac GTPases in inner ear morphogenesis.
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DOI：
10.1016/j.ydbio.2011.12.008
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发表时间：
2012-02-15
影响因子：
2.7
通讯作者：
Lu X
中科院分区：
文献类型：
--
作者：
Grimsley-Myers CM;Sipe CW;Wu DK;Lu X
哺乳动物内耳的发育需要细胞增殖、细胞命运决定和形态发生运动的协调。虽然在识别内耳形成所需的发育信号方面取得了重大进展，但对于不同的信号如何通过其下游介质进行协调却知之甚少。小gtpase的Rac家族成员是已知的细胞骨架重塑和许多其他细胞过程的调节因子。然而，Rac gtp酶在脑发育中的功能在很大程度上尚未被探索。在这里，我们发现Rac1和Rac3冗余调节内耳形态发生的许多方面。而在Rac3-/-小鼠中未观察到形态学缺陷，Rac1CKO；与Rac1CKO单突变体相比，Rac3-/-双突变体表现出更强的前庭和耳蜗畸形。此外，在Rac1CKO；Rac3-/-突变体，我们观察到e -钙粘蛋白介导的细胞粘附受损，细胞增殖减少，细胞死亡增加，导致膜迷路的大小减小和畸形。最后，Rac1CKO患者耳蜗扩展功能严重受损；Rac3-/-突变，伴随着上皮内聚丧失和耳蜗导管下异位感觉斑块的形成。听觉模式基因在Rac1CKO中的区隔表达然而，Rac3-/-突变型耳囊肿在很大程度上是正常的，这表明Rac蛋白在不影响细胞命运规范的情况下调节内耳形态发生。综上所述，我们的研究结果揭示了Rac gtpase在胚胎发育过程中协调细胞粘附、细胞增殖、细胞死亡和细胞运动方面的重要作用。
Development of the mammalian inner ear requires coordination of cell proliferation, cell fate determination and morphogenetic movements. While significant progress has been made in identifying developmental signals required for inner ear formation, less is known about how distinct signals are coordinated by their downstream mediators. Members of the Rac family of small GTPases are known regulators of cytoskeletal remodeling and numerous other cellular processes. However, the function of Rac GTPases in otic development is largely unexplored. Here, we show that Rac1 and Rac3 redundantly regulate many aspects of inner ear morphogenesis. While no morphological defects were observed in Rac3-/- mice, Rac1CKO; Rac3-/- double mutants displayed enhanced vestibular and cochlear malformations compared to Rac1CKO single mutants. Moreover, in Rac1CKO; Rac3-/- mutants, we observed compromised E-cadherin-mediated cell adhesion, reduced cell proliferation and increased cell death in the early developing otocyst, leading to a decreased size and malformation of the membranous labyrinth. Finally, cochlear extension was severely disrupted in Rac1CKO; Rac3-/-mutants, accompanied by a loss of epithelial cohesion and formation of ectopic sensory patches underneath the cochlear duct. The compartmentalized expression of otic patterning genes within the Rac1CKO; Rac3-/- mutant otocyst was largely normal, however, indicating that Rac proteins regulate inner ear morphogenesis without affecting cell fate specification. Taken together, our results reveal an essential role for Rac GTPases in coordinating cell adhesion, cell proliferation, cell death and cell movements during otic development.
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影响因子：
10.5
作者：
Habas, R;Dawid, IB;He, X
通讯作者：
He, X
DOI：
10.1523/jneurosci.3998-09.2009
发表时间：
2009-12-16
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Grimsley-Myers CM;Sipe CW;Géléoc GS;Lu X
通讯作者：
Lu X
DOI：
10.1083/jcb.201009141
发表时间：
2011-03-21
期刊：
The Journal of cell biology
影响因子：
--
作者：
Baum B;Georgiou M
通讯作者：
Georgiou M
影响因子：
4.8
作者：
Haataja, L;Groffen, J;Heisterkamp, N
通讯作者：
Heisterkamp, N
影响因子：
2.7
作者：
Brigande, JV;Iten, LE;Fekete, DM
通讯作者：
Fekete, DM