ABNORMALITIES OF FLOOR PLATE, NOTOCHORD AND SOMITE DIFFERENTIATION INTHE LOOP-TAIL (LP) MOUSE - A MODEL OF SEVERE NEURAL-TUBE DEFECTS

Mouse embryos homozygous for the loop-tail (Lp) mutation fail to initi ate neural tube closure at E8.5, leading to a severe malformation in w hich the neural tube remains open from midbrain to tail. During initia tion of closure, the normal mouse neural plate bends sharply in the mi dline, at the site of the future floor plate. In contrast, Lp/Lp embry os exhibit a broad region of flat neural plate in the midline, displac ing the sites of neuroepithelial bending to more lateral positions. So nic hedgehog (Shh) and Netrin1 are expressed in abnormally broad domai ns in the ventral midline of the E9.5 Lp/Lp neural tube, suggesting ov er-abundant differentiation of the floor plate. The notochord is also abnormally broad in Lp/Lp embryos with enlarged domains of Shh and Bra chyury expression. The paraxial mesoderm shows evidence of ventralisat ion, with increased expression of the sclerotomal marker Pax1, and dim inished expression of the dermomyotomal marker Pax3. While the express ion domain of Pax3 does not differ markedly from wild-type, there is a dorsal shift in the domain of Pax6 expression in the neural tube at c audal levels of Lp/Lp embryos. We suggest that the Lp mutation causes excessive differentiation of floor-plate and notochord, with over-prod uction of Shh from these midline structures causing ventralisation of the paraxial mesoderm and, to a lesser extent, the neural tube. Compar ison with other mouse mutants suggests that the enlarged floor plate m ay be responsible for the failure of neural tube closure in Lp/Lp embr yos. (C) 1998 Elsevier Science Ireland Ltd.