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 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.
Schaapveld
R Q
RQ
Institute of Cellular Signalling, University of Nijmegen, Adelbertusplein 1, Nijmegen, 6525 EK, The Netherlands.
Schepens
J T
JT
Robinson
G W
GW
Attema
J
J
Oerlemans
F T
FT
Fransen
J A
JA
Streuli
M
M
Wieringa
B
B
Hennighausen
L
L
Hendriks
W J
WJ
D000818:Animals; D015152:Blotting, Northern; D015139:Blotting, Southern; D002454:Cell Differentiation; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D006651:Histocytochemistry; D007774:Lactation; D008297:Male; D008321:Mammary Glands, Animal / Q000166:cytology / Q000201:enzymology / Q000254:growth & development*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins; D011247:Pregnancy; D017027:Protein Tyrosine Phosphatases; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic
D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D017027:Protein Tyrosine Phosphatases; C000709129:Ptprf protein, mouse; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2