Transgenic Mouse Approaches for Analysis of the Nervous System

Abstract

The transgenic mouse technology offers the opportunity to introduce or to replace genetic information in the mouse germ line. We discuss the advantages and limitations of the various methods of creating transgenic animals as well as their potential applications to the study of gene regulation and function in the nervous system. We present applications of reporter genes, such as LacZ, whose activity is detectable in situ with histochemical staining, to elucidate the molecular signals controlling the spatial and temporal expression of genes during neurogenesis. The transgenic system offers a unique way of examining in vivo the mechanisms modulating gene expression during neural regeneration. Once transgenic mouse lines are established with a variety of DNA constructs, the cis-regulatory elements involved in up- or down-regulation of a transgene can be examined in vivo after axotomy. Different strategies for realizing the gain or loss of gene activity can provide information on the function of gene products. To direct expression of genes to different cell types in the nervous system, different promoters are now available. Examples of transgenic mice with overt phenotypes are presented, namely, mice exhibiting motor neuronopathy as a result of expression of a neurofilament transgene and mice with aberrant sprouting of sensory axons in the spinal cord as a result of constitutive expression of a NGF construct. The approaches used to abolish partial or complete gene function are addressed. Recent reports of gene knockout experiments with phenotypes such as abnormal sensory innervation (p75NGFR), learning deficits (α-calcium-calmodulin kinase II), or loss of specific CNS regions during development (Wnt-1) illustrate the great potential of the gene-targeting approach for analyzing complex neural functions and for deriving new animal models for human neurological disorders.