IMPAIRED MAMMARY-GLAND DEVELOPMENT AND FUNCTION IN MICE LACKING LAR RECEPTOR-LIKE TYROSINE PHOSPHATASE-ACTIVITY

The LAR receptor-like protein tyrosine phosphatase is composed of two intracellular tyrosine phosphatase domains and a cell adhesion molecul e-like extracellular region containing three immunoglubulin-like domai ns in combination with eight fibronectin type-III like repeats. This a rchitecture suggests that LAR may function in cellular signalling by t he regulation of tyrosine phosphorylation through cell-cell or cell-ma trix interactions. We used gene targeting in mouse embryonic stem cell s to generate mice lacking sequences encoding both LAR phosphatase dom ains, Northern blot analysis of various tissues revealed the presence of a truncated LAR mRNA lacking the cytoplasmic tyrosine phosphatase d omains and indicated that this LAR mutation is not accompanied by obvi ous changes in the expression levels of one of the LAR-like receptor t yrosine phosphatases PTP delta or PTP sigma. LAR(-/-) mice develop and grow normally and display no appreciable histological tissue abnormal ities. However, upon breeding we observed an abnormal neonatal death r ate for pups from LAR(-/-) females. Mammary glands of LAR(-/-) females were incapable of delivering milk due to an impaired terminal differe ntiation of alveoli at late pregnancy. As a result, the glands failed to switch to a lactational state and showed a rapid involution postpar tum. In wild-type mice, LAR expression is regulated during pregnancy r eaching maximum levels around Day 16 of gestation. Taken together, the se findings suggest an important role for LAR-mediated signalling in m ammary gland development and function, (C) 1997 Academic Press.