Transgenic analysis of central nervous system development and regeneration

The transgenic technique allows specific genetic alterations to be made in all cells of an animal and this has greatly improved our understanding of how the embryonic and adult central nervous system (CNS) develop. The CNS originates from the neuroectoderm in the neural plate on the dorsal side of the embryo and after closure of the neural tube the cells of the neuroepithelium, i.e. the CNS stem cells, transiently proliferate to generate neurons and glial cells. Here we review our attempts to gain insights into the control of CNS development. We have identified a gene, nestin, which is predominantly expressed in embryonic and adult CNS stem cells. In addition to its normal expression in the CNS stem cells, nestin is reexpressed in CNS tumors and in the adult spinal cord and brain after CNS injury. By using the lacZ reporter gene assay in transgenic mice, we have identified regulatory regions (enhancer) in the nestin gene required for expression in embryonic CNS stem cells and in the adult spinal cord after injury. In a second project, we have cloned and characterized the Notch gene family (the Notch 1, 2 and 3 genes) in mouse and man. These genes encode trans-membrane receptors, which appear to be key regulatory molecules for proliferation and differentiation both in the developing CNS and in other tissues. Expression of an activated form of the Notch 3 receptor from the nestin promoter in transgenic mice leads to a lethal, exencephaly-like phenotype in the embryo, probably as a result of excess proliferation of the CNS stem cells. The recent finding that the Notch 3 gene is the genetic cause for familial stroke is discussed in the context of current models for Notch function.