Telencephalon-specific Rb knockouts reveal enhanced neurogenesis, survival and abnormal cortical development
Telencephalon-specific Rb knockouts reveal enhanced neurogenesis, survival and abnormal cortical development
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DOI：
10.1093/emboj/cdf338
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发表时间：
2002-07-01
期刊：
影响因子：
11.4
通讯作者：
Slack, RS
中科院分区：
文献类型：
--
作者：
Ferguson, KL;Vanderluit, JL;Slack, RS
正确的细胞周期调控和终末有丝分裂对神经系统发育至关重要。视网膜母细胞瘤(RB)蛋白是这些过程的关键调节因子，因为RB-/-胚胎在E15.5之前死亡，表现出严重的造血和神经缺陷。RB-/-胚胎中广泛的细胞凋亡被归因于异常的S时相进入，导致分化细胞中相互冲突的生长控制信号。为了在没有其他胚胎缺陷的情况下评估Rb在皮质发育中的作用，我们研究了端脑特异性Rb缺失的小鼠。携带Rb等位基因的动物与cre被敲入FOXG1基因座的小鼠杂交。与生殖系基因敲除不同，在发育中的端脑中特定缺失Rb的小鼠存活到出生。在这些突变体中，RB-/-祖细胞异位分裂，但能够存活和分化。由于神经母细胞的增殖增加，突变的大脑表现出更强的细胞性。这些研究表明：(I)在分化过程中细胞周期的放松并不一定需要细胞凋亡；(Ii)Rb基因缺陷的突变体表现出增强的神经母细胞增殖；(Iii)末端有丝分裂可能不是启动分化所必需的。
Correct cell cycle regulation and terminal mitosis are critical for nervous system development. The retinoblastoma (Rb) protein is a key regulator of these processes, as Rb-/- embryos die by E15.5, exhibiting gross hematopoietic and neurological defects. The extensive apoptosis in Rb-/- embryos has been attributed to aberrant S phase entry resulting in conflicting growth control signals in differentiating cells. To assess the role of Rb in cortical development in the absence of other embryonic defects, we examined mice with telencephalon-specific Rb deletions. Animals carrying a floxed Rb allele were interbred with mice in which cre was knocked into the Foxg1 locus. Unlike germline knockouts, mice specifically deleted for Rb in the developing telencephalon survived until birth. In these mutants, Rb-/- progenitor cells divided ectopically, but were able to survive and differentiate. Mutant brains exhibited enhanced cellularity due to increased proliferation of neuroblasts. These studies demonstrate that: (i) cell cycle deregulation during differentiation does not necessitate apoptosis; (ii) Rb-deficient mutants exhibit enhanced neuroblast proliferation; and (iii) terminal mitosis may not be required to initiate differentiation.