Retinoic acid controls early neurogenesis in the developing mouse cerebral cortex
Retinoic acid controls early neurogenesis in the developing mouse cerebral cortex
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DOI：
10.1016/j.ydbio.2017.08.006
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发表时间：
2017-10-01
影响因子：
2.7
通讯作者：
Rhinn, Muriel
中科院分区：
文献类型：
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作者：
Haushalter, Carole;Asselin, Laure;Rhinn, Muriel
神经元产生的严格调节是产生功能性大脑皮层所必需的，并且通过祖细胞增殖和分化之间的适当平衡来实现。虽然维生素A（视黄酸）活性衍生物视黄酸（RA）已被认为是哺乳动物前脑神经发生过程中起作用的信号之一，但其在神经发生开始时以及在皮质层和神经元亚型建立期间的功能仍然是难以捉摸的。一个限制是，鼠突变体的基因编码的关键酶参与RA合成死亡在早期胚胎发育。我们分析了Rdh10无效突变体中的皮质生成，其中RA缺陷是由于细胞内的视网膜到视黄醇的转换被废除而产生的。当在致死性发生之前的最后阶段（胚胎日龄13.5）进行分析时，突变体显示出更小的端脑囊泡，其皮质板的厚度强烈减少。在皮质板中形成的第一祖细胞是放射状神经胶质（RG）细胞，其直接产生神经元，或通过涉及中间神经元祖细胞（INPs）的产生的间接机制产生神经元，所述中间神经元祖细胞随后产生神经元。我们发现，在没有RA的情况下，RG祖细胞增殖较少，过早地产生神经元，导致它们在E11.5耗尽。此外，我们可以证明，RA的缺乏削弱了在E13.5的INPs的产生，并影响皮质生成过程中祖细胞的细胞周期退出，从而导致投射神经元的缺陷和小头畸形。
A tight regulation of neuron production is required to generate a functional cerebral cortex and is achieved by a proper balance between proliferation and differentiation of progenitor cells. Though the vitamin A (retinal) active derivative retinoic acid (RA) has been implicated as one of the signals acting during mammalian forebrain neurogenesis, its function at the onset of neurogenesis as well as during establishment of cortical layers and neuronal subtypes remains elusive. One limitation is that murine mutants for genes encoding key enzymes involved in RA synthesis die during early embryonic development. We analysed corticogenesis in Rdh10 null mutants, in which an RA deficiency is generated as the intracellular retinal to retinaldehyde conversion is abolished. When analysed at the latest stage before lethality occurs (embryonic day [[Epsilon]13.5), the mutants show smaller telencephalic vesicles and the thickness of their cortical plate is strongly reduced. The first progenitors formed in the cortical plate are radial glial (RG) cells which generate neurons either directly, or through an indirect mechanism involving the production of intermediate neuronal progenitors (INPs) which then give rise to neurons. We show that in absence of RA, the RG progenitors proliferate less and prematurely produce neurons, leading to their depletion at E11.5. Furthermore, we could demonstrate that lack of RA impairs the generation of INPs at E13.5 and affects the cell cycle exit of progenitor cells during corticogenesis, altogether leading to a deficit in projection neurons and to microcephaly.