Defective ciliogenesis, embryonic lethality and severe impairment of the Sonic Hedgehog pathway caused by inactivation of the mouse complex A intraflagellar transport gene Ift122/Wdr10, partially overlapping with the DNA repair gene Med1/Mbd4.
Defective ciliogenesis, embryonic lethality and severe impairment of the Sonic Hedgehog pathway caused by inactivation of the mouse complex A intraflagellar transport gene Ift122/Wdr10, partially overlapping with the DNA repair gene Med1/Mbd4.
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DOI：
10.1016/j.ydbio.2008.10.020
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发表时间：
2009-01-01
影响因子：
2.7
通讯作者：
Bellacosa, Alfonso
中科院分区：
文献类型：
--
作者：
Cortellino, Salvatore;Wang, Chengbing;Wang, Baolin;Bassi, Maria Rosaria;Caretti, Elena;Champeval, Delphine;Calmont, Amelie;Jarnik, Michal;Burch, John;Zaret, Kenneth S.;Larue, Lionel;Bellacosa, Alfonso
关键词：
初级纤毛由进化上保守的鞭毛内转运(IFT)蛋白组装和维持，IFT蛋白参与大分子货物从基体到纤毛尖端和背部的协调运动。IFT机制由两个结构复合体组成，分别称为复合体A和复合体B。最近，在小鼠胚系中，属于复合体B的IFT基因的失活揭示了哺乳动物纤毛发生或纤毛发生相关蛋白对Sonic Hedgehog(Shh)信号的要求。在这里，我们报告了一个复杂的A突变小鼠，Ift122基因缺陷。Ift122缺失的胚胎表现出多种发育缺陷(脑外畸形、内脏倒位、转身延迟、出血和肢体发育缺陷)，从而导致死亡。在节部，纯合突变胚初生纤毛缺失或畸形，杂合胚初生纤毛畸形。Shh通路的损害在神经管模式(运动神经元的扩张和吻尾水平依赖的背外侧中间神经元的收缩或扩张)和肢体模式(外合指)中都很明显。这些表型既不同于复杂的B IFT突变胚胎，也不同于纤毛蛋白Hennin/Arl13b缺陷的胚胎，表明Gli2/Gli3激活因子和Gli3抑制因子功能水平降低。我们得出结论，复合A和复合B因子在纤毛发生和Shh/Gli3信号转导中起着相似但不同的作用。
Primary cilia are assembled and maintained by evolutionarily conserved intraflagellar transport (IFT) proteins that are involved in the coordinated movement of macromolecular cargo from the basal body to the cilium tip and back. The IFT machinery is organized in two structural complexes named complex A and complex B. Recently, inactivation in the mouse germline of Ift genes belonging to complex B revealed a requirement of ciliogenesis, or proteins involved in ciliogenesis, for Sonic Hedgehog (Shh) signaling in mammals. Here we report on a complex A mutant mouse, defective for the Ift122 gene. Ift122-null embryos show multiple developmental defects (exencephaly, situs viscerum inversus, delay in turning, hemorrhage and defects in limb development) that result in lethality. In the node, primary cilia were absent or malformed in homozygous mutant and heterozygous embryos, respectively. Impairment of the Shh pathway was apparent in both neural tube patterning (expansion of motoneurons and rostro-caudal level-dependent contraction or expansion of the dorso-lateral interneurons), and limb patterning (ectrosyndactyly). These phenotypes are distinct from both complex B IFT mutant embryos and embryos defective for the ciliary protein hennin/Arl13b, and suggest reduced levels of both Gli2/Gli3 activator and Gli3 repressor functions. We conclude that complex A and complex B factors play similar but distinct roles in ciliogenesis and Shh/Gli3 signaling.
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DOI：
10.1073/pnas.2334585100
发表时间：
2003-12-09
影响因子：
11.1
作者：
Cortellino, S;Turner, D;Bellacosa, A
通讯作者：
Bellacosa, A
影响因子：
30.8
作者：
HUI, CC;JOYNER, AL
通讯作者：
JOYNER, AL
影响因子：
2.7
作者：
Chiang, C;Litingtung, Y;Fallon, JF
通讯作者：
Fallon, JF
影响因子：
3.3
作者：
Händel, M;Schulz, S;Höllt, V
通讯作者：
Höllt, V
影响因子：
64.8
作者：
Corbit, KC;Aanstad, P;Reiter, JF
通讯作者：
Reiter, JF