Tian Yanmei, Lei Liang, Cammarano Marta, Nekrasova Tanya, Minden Audrey
Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854, USA.
Mech Dev. 2009 Aug-Sep;126(8-9):710-20. doi: 10.1016/j.mod.2009.05.002. Epub 2009 May 21.
Pak4 is a member of the group B family of Pak serine/threonine kinases, originally identified as an effector protein for the Rho GTPase Cdc42. Pak4 knockout mice are embryonic lethal and do not survive past embryonic day 11.5. Previous work on Pak4 knockout mice has focused on studying the phenotype of the embryo. Abnormalities in the extraembryonic tissue, however, are common causes of early embryonic death in knockout mice. Extraembryonic tissue associated with the Pak4-null embryos was therefore examined. Abnormalities in both yolk sacs and placentas resulted when Pak4 was deleted. These included a lack of vasculature throughout the extraembryonic tissue, as well as an abnormally formed labyrinthine layer of the placenta. Interestingly, epiblast-specific deletion of Pak4 using a conditional knockout system, did not rescue the embryonic lethality. In fact, it did not even rescue the extraembryonic tissue defects. Our results suggest that the extraembryonic tissue abnormalities are secondary to defects that occur in response to epiblast abnormalities. More detailed analysis suggests that abnormalities in vasculature throughout the extraembryonic tissue and the epiblast may contribute to the death of the Pak4-null embryos.
Pak4是Pak丝氨酸/苏氨酸激酶B族的成员，最初被鉴定为Rho GTP酶Cdc42的效应蛋白。Pak4基因敲除小鼠在胚胎期致死，无法存活至胚胎第11.5天以后。先前对Pak4基因敲除小鼠的研究主要集中在胚胎表型上。然而，胚外组织异常是基因敲除小鼠早期胚胎死亡的常见原因。因此，对与Pak4基因敲除胚胎相关的胚外组织进行了检查。当Pak4被敲除时，卵黄囊和胎盘均出现异常。这些异常包括整个胚外组织缺乏血管，以及胎盘迷路层形成异常。有趣的是，使用条件性基因敲除系统在原始外胚层特异性敲除Pak4，并不能挽救胚胎致死性。事实上，它甚至不能挽救胚外组织缺陷。我们的结果表明，胚外组织异常继发于对原始外胚层异常做出反应而出现的缺陷。更详细的分析表明，整个胚外组织和原始外胚层的血管异常可能导致Pak4基因敲除胚胎死亡。
