Disruption of the gene for a subunit of a nitric oxide-sensitive form of soluble guanylyl cyclase.

A soluble form of guanylyl cyclase containing the alpha 1 and beta 1 subunits appears to mediate nitric oxide-dependent elevations of cyclic GMP and therefore may account for many of the phenotypes associated with NO-dependent signaling. Prominent target tissues include smooth muscle of the vasculature and platelets. Also, since other apparent soluble guanylyl cyclase subunits appear to exist, disruption of the gene may address the specific importance of the beta1/alpha1 subunits. The endogenous gene for the beta 1 subunit was disrupted in embryonic stem cells using homologous recombination to insert a neomycin-resistance gene into a region of the beta 1 subunit gene just to the 5′-side of the conserved catalytic region. The embryonic stem cells were then subsequently injected into blastocysts, and based on fur coat color, a number of the male pups have a contribution of greater than 90% ES cells. These animals are now being mated to obtain lines showing germ-line transmission.