Neurale Stammzellen des adulten Gehirns: Transdifferenzierung und Rekrutierung ependymaler und endothelialer Zellen

越来越多的证据表明，成年哺乳动物的大脑中存在神经干细胞。到目前为止，至少已经确定了三个“神经源性区域”，即脑室下区、海马体和嗅球。我们之前的观察表明，血管生成因子血管内皮生长因子(VEGF)，以前被认为几乎只作用于心血管系统，是成人干细胞活动和神经发生的调节因子。为了具体验证这一假设，我们计划利用条件失活血管内皮生长因子基因的遗传小鼠模型。我们计划使用VEGFlox/lox-GFAPcre小鼠，由于crerecombinase的特定活性，这些小鼠在出生时不在神经细胞中表达VEGF。由于星形胶质细胞和神经元是出生后大脑中血管内皮生长因子的主要制造者，这个遗传模型将使我们能够测试血管内皮生长因子在成人神经干细胞功能中的假定作用。我们以前的研究结果也表明，血管内皮生长因子的神经发生作用是由血管内皮生长因子-R2介导的。为了排除血管内皮生长因子的另一个酪氨酸激酶受体，血管内皮生长因子-R1的可能作用，我们计划研究胎盘生长因子基因(P1GF)纯合子缺失的小鼠。P1GF只与VEGFR-1结合，而不与VEGFR-2结合，而VEGF与VEGFR-1和-R-2结合。综上所述，这两个转基因小鼠模型将使我们能够剖析血管内皮生长因子在成人神经干细胞中可能扮演的角色，并识别涉及的受体。

There is accummulating evidence that neural stem cells exist in the adult mammalian brain. To date, at least three "neurogenic regions" habe been identified, namely the subventricular zone, the hippocampus and the olfactory bulb. Our previous observations suggest that the angiogenesis factor vascular endothelial growth factor (VEGF), previously thought to act almost exclusively on the cardiovascular system, is a regulator of adult stem cell activity and neurogenesis. To specifically test this hypothesis, we plan to make use of genetic mouse models with conditional inactivation of the VEGF gene. We plan to use VEGF lox/lox-GFAPcre mice which-due to the specific activity of crerecombinase-do not express VEGF in neural cells commencing birth. Since astrocytes and neurons are main producers of VEGF in the brain after birth, this genetic model will allow us to test the putative role of VEGF in adult neural stem cell function. Our previous findings also suggest, that the neurogenic effect of VEGF is mediated by VEGF-R2. To rule out a possible role of the other tyrosine kinase receptor for VEGF, VEGF-R1, we plan to investigate mice with a homozygous deletion of the placenta growth factor gene (P1GF). P1GF only binds to VEGFR-1 but not to VEGFR-2, in contrast to VEGF, which binds to VEGFR-1 and -R-2. Taken together, these two transgenic mouse models will allow us to dissect the putative role VEGF may have in adult neural stem cells and to identify the receptors involved.