Perlecan controls neurogenesis in the developing telencephalon
Perlecan controls neurogenesis in the developing telencephalon
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DOI：
10.1186/1471-213x-7-29
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发表时间：
2007-04-05
影响因子：
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通讯作者：
Costell, Mercedes
中科院分区：
文献类型：
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作者：
Giros, Amparo;Morante, Javier;Costell, Mercedes
背景：基底膜蛋白聚糖是一种在发育过程中在神经上皮基底层表达的蛋白多糖。基底膜蛋白缺失不会损害基底层组装，尽管在 55% 的突变体中，该基底层的早期破坏会导致脑外畸形，损害大脑发育。其余的基底膜蛋白缺失的大脑完成其产前发育，维持被一些孤立的异位中断的基底层连续性，并且是小头的。小头畸形由较薄的脑壁和不发达的神经节隆起组成。我们研究了在基底层完整的端脑区域产生脑萎缩的机制。结果：在缺乏基底膜蛋白的情况下，脑萎缩从腹侧前脑开始，并在以下阶段扩展到皮质的外侧和背侧部分。首先，在早期无基底膜蛋白的胚胎中，由于细胞增殖减少，皮质下前脑发育不良：自发育早期阶段以来，有丝分裂中的细胞数量减少。这种减少导致中间神经元向大脑皮层的切向迁移减少。伴随着内侧神经节隆起中观察到的早期发育不全，Sonic Hedgehog 信号在 E12.5 的基底膜缺失底板基底层中减少。其次，基底膜蛋白缺陷胚胎中大脑皮层神经上皮的神经发生受到影响。我们发现 E12-E13 退出细胞周期的细胞数量减少了近 50%。标记指数在这个年龄是正常的，但随着皮质生成的进展而显着下降。此外，巢蛋白（+）或PCNA（+）祖细胞自E14.5以来增加，达到E17.5时野生型中PCNA（+）细胞比例的约150%。因此，标记指数的降低和祖细胞数量的增加表明，萎缩是皮质祖细胞中细胞周期进程改变的结果。因此，从神经元标记 β-微管蛋白和 Tbr1 可以看出，基底膜蛋白无效的新皮质的皮质板和亚板中的神经元较少。结论：作为基底层的组成部分，基底膜蛋白既维持这种结构，又控制神经上皮对生长因子的反应。早期内侧神经节隆起中的有丝分裂细胞较少，以及晚期新皮质中的细胞周期进程受损，表明神经源性形态发生素（例如 SHH 或 FGF2）的募集和信号传导不足。
Background: Perlecan is a proteoglycan expressed in the basal lamina of the neuroepithelium during development. Perlecan absence does not impair basal lamina assembly, although in the 55% of the mutants early disruptions of this lamina conducts to exencephaly, impairing brain development. The rest of perlecan-null brains complete its prenatal development, maintain basal lamina continuity interrupted by some isolated ectopias, and are microcephalic. Microcephaly consists of thinner cerebral walls and underdeveloped ganglionic eminences. We have studied the mechanisms that generate brain atrophy in telencephalic areas where basal lamina is intact.Results: Brain atrophy in the absence of perlecan started in the ventral forebrain and extended to lateral and dorsal parts of the cortex in the following stages. First, the subpallial forebrain developed poorly in early perlecan-null embryos, because of a reduced cell proliferation: the number of cells in mitosis decreased since the early stages of development. This reduction resulted in a decreased tangential migration of interneurons to the cerebral cortex. Concomitant with the early hypoplasia observed in the medial ganglionic eminences, Sonic Hedgehog signal decreased in the perlecan-null floor plate basal lamina at E12.5. Second, neurogenesis in the pallial neuroepithelium was affected in perlecan deficient embryos. We found reductions of nearly 50% in the number of cells exiting the cell cycle at E12-E13. The labeling index, which was normal at this age, significantly decreased with advancing corticogenesis. Moreover, nestin(+) or PCNA(+) progenitors increased since E14.5, reaching up to about 150% of the proportion of PCNA(+) cells in the wild-type at E17.5. Thus, labeling index reduction together with increased progenitor population, suggests that atrophy is the result of altered cell cycle progression in the cortical progenitors. Accordingly, less neurons populated the cortical plate and subplate of perlecan-null neocortex, as seen with the neuronal markers beta-tubulin and Tbr1.Conclusion: As a component of the basal lamina, perlecan both maintains this structure and controls the response of the neuroepithelium to growth factors. Less mitotic cells in the early medial ganglionic eminences, and impaired cell cycle progression in the late neocortex, suggests insufficient recruitment and signaling by neurogenic morphogens, such as SHH or FGF2.