Deletion of the nuclear localization sequences and C-terminus of PTHrP impairs embryonic mammary development but also inhibits PTHrP production.
Parathyroid hormone-related protein (PTHrP) can be secreted from cells and interact with its receptor, the Type 1 PTH/PTHrP Receptor (PTHR1) in an autocrine, paracrine or endocrine fashion. PTHrP can also remain inside cells and be transported into the nucleus, where its functions are unclear, although recent experiments suggest that it may broadly regulate cell survival and senescence. Disruption of either the PTHrP or PTHR1 gene results in many abnormalities including a failure of embryonic mammary gland development in mice and in humans. In order to examine the potential functions of nuclear PTHrP in the breast, we examined mammary gland development in PTHrP (1-84) knock-in mice, which express a mutant form of PTHrP that lacks the C-terminus and nuclear localization signals and which can be secreted but cannot enter the nucleus. Interestingly, we found that PTHrP (1-84) knock-in mice had defects in mammary mesenchyme differentiation and mammary duct outgrowth that were nearly identical to those previously described in PTHrP-/- and PTHR1-/- mice. However, the mammary buds in PTHrP (1-84) knock-in mice had severe reductions in mutant PTHrP mRNA levels, suggesting that the developmental defects were due to insufficient production of PTHrP by mammary epithelial cells and not loss of PTHrP nuclear function. Examination of the effects of nuclear PTHrP in the mammary gland in vivo will require the development of alternative animal models.
Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Kata
K
Boras-Granic
Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Pamela
P
Dann
Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Joshua
J
Vanhouten
Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Canada.
Andrew
A
Karaplis
Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut, United States of America.
John
J
Wysolmerski
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D008321:Mammary Glands, Animal / Q000196:embryology* / Q000254:growth & development / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D019913:Nuclear Localization Signals / Q000235:genetics*; D044162:Parathyroid Hormone-Related Protein / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics*; D010446:Peptide Fragments / Q000235:genetics; D054730:Protein Interaction Domains and Motifs; D012727:Sex Characteristics
D015415:Biomarkers; D019913:Nuclear Localization Signals; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; C066077:parathyroid hormone-related protein (1-84)