Department of Chemical Biology, Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey,164 Frelinghuysen Road, Piscataway, NJ 08854, USA.
Dev Biol. 2011 May 15;353(2):206-16. doi: 10.1016/j.ydbio.2011.02.026. Epub 2011 Mar 4.
The Pak4 serine/threonine kinase regulates cytoskeletal organization, and controls cell growth, proliferation, and survival. Deletion of Pak4 in mice results in embryonic lethality prior to embryonic day 11.5. Pak4 knockout embryos exhibit abnormalities in the nervous system, the heart, and other tissues. In this study a conditional deletion of Pak4 was generated in order to study the function of Pak4 in the development of the brain. Nervous system-specific conditional deletion of Pak4 was accomplished by crossing mice with a floxed allele of Pak4 with transgenic mice expressing Cre recombinase under the control of the nestin promoter. The conditional Pak4 knockout mice were born normally, but displayed growth retardation and died prematurely. The brains showed a dramatic decrease in proliferation of cortical and striatal neuronal progenitor cells. In vitro analyses revealed a reduced proliferation and self-renewing capacity of neural progenitor cells isolated from Pak4 knockout brains. The mice also exhibited cortical thinning, impaired neurogenesis and loss of neuroepithelial adherens junctions. By the time the mice died, by 4weeks after birth, severe hydrocephalus could also be seen. These results suggest that Pak4 plays a critical role in the regulation of neural progenitor cell proliferation and in establishing the foundation for development of the adult brain.
Pak4 丝氨酸/苏氨酸激酶调节细胞骨架组织，并控制细胞生长、增殖和存活。Pak4 在小鼠中的缺失导致胚胎在胚胎第 11.5 天前致死。Pak4 敲除胚胎表现出神经系统、心脏和其他组织的异常。在这项研究中，生成了 Pak4 的条件性缺失，以研究 Pak4 在大脑发育中的功能。通过将带有 Pak4 基因 floxed 等位基因的小鼠与 nestin 启动子控制下表达 Cre 重组酶的转基因小鼠杂交，实现了神经系统特异性条件性 Pak4 缺失。条件性 Pak4 敲除小鼠正常出生，但表现出生长迟缓并过早死亡。大脑显示皮质和纹状体神经元祖细胞的增殖显著减少。体外分析显示，从 Pak4 敲除小鼠大脑中分离出的神经祖细胞增殖减少，自我更新能力降低。这些小鼠还表现出皮质变薄、神经发生受损和神经上皮黏着连接丧失。到小鼠死亡时，即出生后 4 周，还可以看到严重的脑积水。这些结果表明，Pak4 在调节神经祖细胞增殖和为成年大脑发育奠定基础方面发挥着关键作用。
