NEPH/Nephrin proteins regulate connectivity in the vertebrate nervous system.

We have recently extended our studies of Ig domain cell-cell recognition proteins to the vertebrate olfactory system. The mouse genome contains three orthologs of SYG-1, known as NEPH1/Kirrel1, NEPH2/Kirrel3 and NEPH3/Kirrel2, as well as a single ortholog of SYG-2 called Nephrin. All four genes are expressed in subsets of mouse olfactory sensory neurons, and NEPH2 is also present in mitral/tufted neurons within the olfactory bulb, which are the synaptic partners for sensory neurons. Thus NEPH/Nephrin proteins may be regulating synaptic specificity in the mouse olfactory system in an analogous fashion to their orthologs in C. elegans. We have obtained mutant strains for Nephrin, NEPH1 and NEPH2 and are currently investigating neuronal connectivity and synapse formation in these mutants. The figure shows that Nephrin is required for the correct innervation pattern of olfactory sensory neurons; Nephrin-expressing axons are labeled with the LacZ marker which is fused in-frame to the N terminus of Nephrin protein in the knockout allele, and they grow into inappropriate anterior and dorsal regions of the olfactory bulb in mutant mice.

Fig. 5-1Aberrant olfactory axon connectivity in Nephrin mutants. Upper panels show whole mount X-gal stanining for Nephrin ^1A/+ (A) and Nephrin^1A/1A (B) mice at birth. The medial face of the olfactory bulb is outlined by a dotted white line. Lower panels show a representative section stained with X-gal at the approximately same anteroposterior position for Nephrin^1A/+ (C) and Nephrin^1A/S20 (D) mice at age P4. The circumferential extent of Nephrin-positive glomerular innervation is indicated by arrowheads. Dorsal is up, anterior to the right (A, B).