EXPRESSION OF INDIAN HEDGEHOG, BONE MORPHOGENETIC PROTEIN-6 AND GLI DURING SKELETAL MORPHOGENESIS

A complex signaling pathway involving members of the Hedgehog, Bone mo rphogenetic protein (Bmp) and Gli families regulates early patterning events in fetal skeletogenesis (Hui and Joyner, 1993. A mouse model of Greig cephalopolysyndactyly syndrome: the extra-toes mutation contain s an intragenic deletion of the Gli3 gene. Nat. Genet. 3, 241-246; Bit good and McMahon, 1995. Hedgehog and Bmp genes are coexpressed at many diverse sites of cell-cell interaction in the mouse embryo. Dev. Biol . 172, 126-138; Lanske et al., 1996. PTH/PTHrP receptor in early devel opment and Indian hedgehog-regulated bone growth. Science 273, 663-666 ; Vortkamp et al., 1996. Regulation of rate of cartilage differentiati on by Indian hedgehog and PTH-related protein. Science 273, 613-622). Hedgehog genes encode secreted proteins that mediate patterning and gr owth through the induction of secondary signals (reviewed in Hammersch midt et al., 1997. The world according to hedgehog. Trends Genet. 13, 14-21). Two potential targets of Ihh are bmp6 and gli (Johnson et al., 1995. Patched overexpression alters wing disc size and pattern: trans criptional and post-transcriptional effects on hedgehog targets. Devel opment 121, 4161-4170; Dominguez et al., 1996. Sending and receiving t he hedgehog signal: control by the Drosophila Gli protein Cubitus inte rruptus. Science 272, 1621-1625; Marigo et al., 1996. Sonic hedgehog d ifferentially regulates expression of GLI and GLI3 during limb develop ment. Dev. Biol. 180, 273-283). We investigated the molecular similari ties and differences between fetal and postnatal skeletal development by analyzing the coincident and complimentary expression domains of in dian hedgehog (ihh), bmp6 and gli in adjacent sections throughout the process of skeletogenesis. In almost all of the skeletal tissues exami ned, the expression domains of ihh and bmp6 were adjacent to one anoth er and this region was surrounded by gli-expressing cells. These obser vations are in keeping with the proposed function of gli as a negative regulator of Ihh signaling and the induction of Bmps by Hedgehog prot eins (Roberts et al., 1995. Sonic hedgehog is an endodermal signal ind ucing Bmp-4 and Hox genes during induction and regionalization of the chick hindgut. Development 121, 3163-3174; Kawakami et al., 1996. BMP signaling during bone pattern determination in the developing limb. De velopment 122, 3557-3566). By puberty, ihh, bmp6 and gli transcripts w ere no longer detected in the growth plate, despite the fact that phys eal chondrocytes continued to hypertrophy and differentiate. Although bmp6 was expressed, ihh transcripts were not found in primordia of int ramembranous bones, nor in cells lining the future articular surfaces. Collectively our findings suggest that ihh participates in, but is no t required for chondrocyte hypertrophy. (C) 1997 Elsevier Science Irel and Ltd.