PARATHYROID-HORMONE RELATED PROTEIN IS A DEVELOPMENTAL REGULATORY MOLECULE

Parathyroid hormone-related peptide (PTHrP) was discovered as the tumo r product that is responsible for most instances of the syndrome of hu moral hypercalcemia of malignancy. It is now known that the PTHrP and the PTH genes arose on the basis of an ancient duplication event. One result of this heritage is a short stretch of highly homologous sequen ce at the N-terminus of each of the peptides, and another is the fact that these N-terminal products seem to be serviced by a single G prote in-coupled receptor referred to as the type I receptor. Overexpression and null strategies in mich have recently provided convincing evidenc e that one such PTHrP function is as a developmental regulatory molecu le. For example, overexpression of PTHrP in keratinocytes, mammary epi thelial cells and chondrocytes results in a developmental phenotype in each case, while knockout of the gene is associated with a chondrodys trophy that is lethal at birth. Rescue of the PTHrP-null mouse via a g enetic strategy involving a cross between the knockout mouse and a tra nsgenic mouse with targeted PTHrP overexpression in chondrocytes provi des a window on previously unappreciated PTHrP developmental regulator y effects in multiple tissues that share a common epithelial-mesenchym al morphogenetic background.