Zindy F, Soares H, Herzog K H, Morgan J, Sherr C J, Roussel M F
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Cell Growth Differ. 1997 Nov;8(11):1139-50.
In situ hybridization of mouse embryo sections demonstrated expression of mRNAs encoding two polypeptide inhibitors (p18INK4c and p19INK4d) of cyclin D-dependent kinase (CDK) 4 and CDK6 in the central nervous system. No expression of two other INK4 members, p16INK4a and p15INK4b, was observed. The p19INK4d and p18INK4c proteins formed complexes with either CDK4 or CDK6 in a temporal pattern consistent with the results of in situ hybridization. Expression of INK4c was observed at embryonic day 13.5 in neuroepithelial zones of the developing brain, being restricted to dividing neuroblasts but absent from differentiating postmitotic neurons. In the neocortex, p18INK4c was expressed precisely at those developmental stages when neuroblasts switch from a symmetric to an asymmetric pattern of cell division with concomitant increases in their G1 interval. INK4d RNA was detected from embryonic day 11.5 onward, at higher levels than INK4c and with a distinctly different spatial and temporal pattern. Marked INK4d expression was seen in dorsal root ganglia, spinal cord, and focally throughout the brain, but primarily in postmitotic neurons. Neural expression of INK4d continued postnatally into adulthood in postmitotic cells of the dentate gyrus, the pyramidal layer of the hippocampus, and in discrete regions of the cerebral cortex, cerebellum, thalamus, and brainstem. Downregulation of p19INK4d in the dentate gyrus after kainic acid-induced seizures indicated that its expression could also be modified in nondividing cells by excitotoxic stress. Therefore, p19INK4d may contribute to maintaining the quiescent state, acting as a buffer to prevent reactivation of cyclin D-dependent kinases in terminally differentiated cells.
小鼠胚胎切片的原位杂交显示，在中枢神经系统中，编码细胞周期蛋白D依赖性激酶（CDK）4和CDK6的两种多肽抑制剂（p18INK4c和p19INK4d）的mRNA有表达。未观察到另外两种INK4成员p16INK4a和p15INK4b的表达。p19INK4d和p18INK4c蛋白与CDK4或CDK6形成复合物，其时间模式与原位杂交结果一致。在胚胎第13.5天，在发育中大脑的神经上皮区域观察到INK4c的表达，其仅限于正在分裂的神经母细胞，而在分化后的有丝分裂后神经元中不存在。在新皮层中，p18INK4c恰好在神经母细胞从对称细胞分裂模式转变为不对称细胞分裂模式且其G1期同时增加的那些发育阶段表达。从胚胎第11.5天开始检测到INK4d RNA，其水平高于INK4c，并且具有明显不同的时空模式。在背根神经节、脊髓以及全脑局部均可见明显的INK4d表达，但主要在有丝分裂后神经元中。出生后，在齿状回、海马体锥体细胞层以及大脑皮层、小脑、丘脑和脑干的离散区域的有丝分裂后细胞中，INK4d在神经组织中的表达持续至成年期。在 kainic 酸诱导的癫痫发作后，齿状回中p19INK4d的下调表明其表达也可在非分裂细胞中因兴奋性毒性应激而改变。因此，p19INK4d可能有助于维持静止状态，作为一种缓冲剂，防止终末分化细胞中细胞周期蛋白D依赖性激酶的重新激活。
