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

有证据表明神经干细胞存在于成年哺乳动物的大脑中。到目前为止，至少有三个“神经源性区域”已被确定，即脑室下区，海马和嗅球。我们以前的观察表明，血管生成因子血管内皮生长因子（VEGF），以前认为几乎完全作用于心血管系统，是成人干细胞活性和神经发生的调节因子。为了具体地检验这一假设，我们计划利用VEGF基因条件性失活的遗传小鼠模型。我们计划使用VEGF lox/lox-GFAPcre小鼠，由于crerecombinase的特异性活性，这些小鼠在出生后的神经细胞中不表达VEGF。由于星形胶质细胞和神经元是出生后大脑中VEGF的主要生产者，因此这种遗传模型将使我们能够测试VEGF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，VEGF的神经原性作用是由VEGF-R2介导的。为了排除VEGF的其他酪氨酸激酶受体VEGF-R1的可能作用，我们计划研究胎盘生长因子基因（P1 GF）纯合缺失的小鼠。P1 GF仅与VEGFR-1结合，但不与VEGFR-2结合，与VEGF相反，VEGF与VEGFR-1和VEGFR-2结合。两者合计，这两个转基因小鼠模型将使我们能够剖析VEGF可能在成人神经干细胞中的假定作用，并确定相关的受体。

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.