Fig. 1. mte and mitt mouse embryos have limb defects due to mutations in the Lrp4 gene. (A) Schematic diagram of mouse Lrp proteins. Positions of mutations in the mitt and mte alleles of Lrp4 are indicated next to the proposed Lrp4 structure. The intracellular region of Lrp4 contains motifs predicted to mediate clustering to clathrincoated pits and a terminal SXV motif predicted to mediate interactions with PDZ domain-containing proteins. (B-E) E18.5 Limb skeletal preparations highlight the abnormalities in Lrp4^mitt autopods (C,E) compared with wild type (B,D). (B,C) Forelimbs; (D,E) hind limbs. Digit numbers are reduced, phalanges and metacarpals/metatarsals are fused, and ossification is decreased in Lrp4^mitmutant autopods (C,E). At earlier stages of limb development, Lrp4 mutants display AER expansion and a failure of AER refinement and maturation. (F-K) Longitudinal sections through E9.5 limb buds. Dorsal is to the top, distal to the right. Fgf8, a marker of AER cells, is normally restricted to the distal region of E9.5 forelimbs (F), but is expanded both dorsally (red arrowhead) and ventrally (black arrowhead) in Lrp4 mutants (G) and no morphologically distinct AER forms (see Fig. S1 in the supplementary material). In parallel, dorsal expression of Msx2 (H) is expanded in Lrp4 mutants (I, red arrowhead) and there is a loss of Wnt7a in the most distal region of mutant forelimbs (compare K to J).