Impaired Mammary Gland Development and Function in Mice Lacking LAR Receptor-like Tyrosine Phosphatase Activity

Abstract

The LAR receptor-like protein tyrosine phosphatase is composed of two intracellular tyrosine phosphatase domains and a cell adhesion molecule-like extracellular region containing three immunoglubulin-like domains in combination with eight fibronectin type-III-like repeats. This architecture suggests that LAR may function in cellular signalling by the regulation of tyrosine phosphorylation through cell-cell or cell-matrix interactions. We used gene targeting in mouse embryonic stem cells to generate mice lacking sequences encoding both LAR phosphatase domains. Northern blot analysis of various tissues revealed the presence of a truncated LAR mRNA lacking the cytoplasmic tyrosine phosphatase domains and indicated that this LAR mutation is not accompanied by obvious changes in the expression levels of one of the LAR-like receptor tyrosine phosphatases PTPdelta or PTPsigma. LAR-/- mice develop and grow normally and display no appreciable histological tissue abnormalities. However, upon breeding we observed an abnormal neonatal death rate for pups from LAR-/- females. Mammary glands of LAR-/- females were incapable of delivering milk due to an impaired terminal differentiation of alveoli at late pregnancy. As a result, the glands failed to switch to a lactational state and showed a rapid involution postpartum. In wild-type mice, LAR expression is regulated during pregnancy reaching maximum levels around Day 16 of gestation. Taken together, these findings suggest an important role for LAR-mediated signalling in mammary gland development and function.

Expression of dominant-negative ErbB2 in the mammary gland of transgenic mice reveals a role in lobuloalveolar development and lactation

“…Independent laboratories reported that Stat5a (Liu et al, 1996;Teglund et al, 1998) and LAR (Schaapveld et al, 1997) are required for normal lobuloalveolar maturation and lactation at parturition. The possible coupling of ErbB2 signaling with the signaling pathways of Stat5a and LAR or both, deserves further investigation.…”

Think globally, act locally: the making of a mouse mammary gland

“…Normal mammary morphogenesis but impaired function is observed in the absence of the cytoplasmic phosphatase LAR (Schaapveld et al 1997). Although the molecular basis of this defect is unclear, it has been shown that LAR is found in focal adhesion sites.…”

“…Less clear are some of the signaling events leading to the functional differentiation of the epithelium. In particular, the roles which CSF-1 (Pollard and Hennighausen 1994) and LAR (Schaapveld et al 1997) play in the mammary gland need to be defined.…”

“…Johnson, and L. Hennighausen, in prep. ); (Stat5a) Signal transducer and activator of transcription (Liu et al 1997); (PR) Progesterone receptor (Lydon et al 1995), A-myb (Toscani et al 1997); cyclin D1 (Fantl et al 1995;Sicinski et al 1995); (CSF-1) macrophage specific colony stimulating factor 1 (Pollard and Hennighausen 1994); LAR (Schaapveld et al 1997); Mf3 (Labosky et al 1997); oxytocin (Wagner et al 1997a). …”

The transmembrane protein tyrosine phosphatase RPTPσ modulates signaling of the epidermal growth factor receptor in A431 cells

“…The PTPs in this family exhibit extracellularly structural features characteristic of adhesion molecules and reveal a high degree of homology to each other suggesting that they may partially be redundant with respect to function. This assumption is supported by the ®nding that mice with an inactivated LAR gene are viable and have a more subtle phenotype in mammary gland development (Skarnes et al, 1995;Schaapveld et al, 1997b). On the other hand, the PTPs in this family exist in multiple isoforms arising by alternative splicing, suggesting possibly very speci®c functions in dierent cell types or developmental stages (Longo et al, 1993;Ogrady et al, 1994;Rotin et al, 1994;Zhang and Longo, 1995;Pulido et al, 1995a).…”