Severe neural tube defects in the loop-tail mouse result from mutation of Lpp1, a novel gene involved in floor plate specification

Neural tube defects (NTD) are clinically important congenital malformations whose molecular mechanisms are poorly understood. The loop-tail (Lp) mutan t mouse provides a model for the most severe NTD, craniorachischisis, in wh ich the brain and spinal cord remain open. During a positional cloning appr oach, we have identified a mutation in a novel gene, Lpp1, in the Lp mouse, providing a strong candidate for the genetic causation of craniorachischis is in Lp. Lpp1 encodes a protein of 521 amino acids, with four transmembran e domains related to the Drosophila protein strabismus/van gogh (vang). The human orthologue, LPP1, shares 89% identity with the mouse gene at the nuc leotide level and 99% identity at the amino acid level. Lpp1is expressed in the ventral part of the developing neural tube, but is excluded from the f loor plate where Sonic hedgehog(Shh) is expressed. Embryos lacking Shh expr ess Lpp1 throughout the ventral neural tube, suggesting negative regulation of Lpp1 by Shh. Our findings suggest that the mutual interaction between L pp1 and Shh may define the lateral boundary of floor plate differentiation. Loss of Lpp1function disrupts neurulation by permitting more extensive flo or plate induction by Shh, thereby inhibiting midline bending of the neural plate during initiation of neurulation.