Developmental expression of MARCKS and protein kinase C in mice in relation to the exencephaly resulting from MARCKS deficiency
Developmental expression of MARCKS and protein kinase C in mice in relation to the exencephaly resulting from MARCKS deficiency
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DOI：
10.1016/0165-3806(96)00097-1
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发表时间：
1996-10-23
期刊：
影响因子：
--
通讯作者：
Sulik, KK
中科院分区：
文献类型：
--
作者：
Blackshear, PJ;Lai, WS;Sulik, KK
人们对蛋白激酶 C 及其底物在发育中的作用知之甚少。最近，我们破坏了小鼠蛋白激酶 C 主要细胞底物 MARCKS 蛋白的基因（Proc. Natl. Acad. Sci. USA, 92, 944-948, 1995）。由此产生的表型包括普遍的围产期致死率、胼胝体和其他前脑连合发育不全、神经元异位和其他皮质和视网膜层压紊乱。这些小鼠的无脑畸形发生率也很高（总体为 25%，雌性为 35%）。在本研究中，我们检测了颅神经管闭合时MARCKS和蛋白激酶C的各种同工酶的正常表达，试图将MARCKS表达的时间和解剖位置与MARCKS缺陷的脑外特征联系起来。神经管闭合失败发生在颅神经管的多个部位，表明细胞功能缺陷不限于特定部位。非脑外 MARCKS 缺陷胚胎在胚胎第 (E) 8.5-9.5 天似乎在解剖学上正常。 MARCKS 和 PKC α 在构成未来神经管的神经上皮细胞的质膜以及表面外胚层和下面的间充质中表达。包含α和δ之一或两者的内源蛋白激酶C种类能够磷酸化完整E8.5胚胎中的MARCKS。因此，MARCKS 在参与颅神经形成的特定细胞类型的质膜上表达；它的缺陷可能会导致这些细胞出现尚待阐明的功能缺陷，从而导致大部分病例出现脑外畸形。
The roles of protein kinase C and its substrates in development are poorly understood. Recently, we disrupted the mouse gene for a major cellular substrate for protein kinase C, the MARCKS protein (Proc. Natl. Acad. Sci. USA, 92, 944-948, 1995). The resulting phenotype consisted of universal perinatal lethality, agenesis of the corpus callosum and other forebrain commissures, and neuronal ectopia and other cortical and retinal lamination disturbances. These mice also had high frequencies of exencephaly (25% overall, 35% in females). In the present study, we have examined the normal expression of MARCKS and the various isozymes of protein kinase C at the time of cranial neural tube closure, in an attempt to correlate MARCKS expression in time and anatomical location with the exencephaly characteristic of MARCKS deficiency. Failure of neural tube closure occurred at various sites in the cranial neural tube, suggesting a cellular functional defect that was not limited Co a specific location. Non-exencephalic MARCKS-deficient embryos appeared to be anatomically normal on embryonic day (E) 8.5-9.5. MARCKS and PKC alpha were expressed at the plasma membrane of the neuroepithelial cells comprising the future neural tube, as well as in the surface ectoderm and underlying mesenchyme. Endogenous protein kinase C species, comprising either or both alpha and delta, were capable of phosphorylating MARCKS in intact E8.5 embryos. Thus, MARCKS is expressed at the plasma membranes of the specific cell types involved In cranial neurulation; its deficiency presumably results in a still-to-be-elucidated functional defect in these cells that leads to exencephaly in a high proportion of cases.