Defective prolactin signaling impairs pancreatic β-cell development during the perinatal period.
Prolactin (PRL) and placental lactogens stimulate β-cell replication and insulin production in pancreatic islets and insulinoma cells through binding to the PRL receptor (PRLR). However, the contribution of PRLR signaling to β-cell ontogeny and function in perinatal life and the effects of the lactogens on adaptive islet growth are poorly understood. We provide evidence that expansion of β-cell mass during both embryogenesis and the postnatal period is impaired in the PRLR(-/-) mouse model. PRLR(-/-) newborns display a 30% reduction of β-cell mass, consistent with reduced proliferation index at E18.5. PRL stimulates leucine incorporation and S6 kinase phosphorylation in INS-1 cells, supporting a role for β-cell mTOR signaling in PRL action. Interestingly, a defect in the development of acini is also observed in absence of PRLR signaling, with a sharp decline in cellular size in both endocrine and exocrine compartments. Of note, a decrease in levels of IGF-II, a PRL target, in the Goto-Kakizaki (GK) rat, a spontaneous model of type 2 diabetes, is associated with a lack of PRL-mediated β-cell proliferation in embryonic pancreatic buds. Reduced pancreatic IGF-II expression in both rat and mouse models suggests that this factor may constitute a molecular link between PRL signaling and cell ontogenesis. Together, these results provide evidence that PRL signaling is essential for pancreas ontogenesis during the critical perinatal window responsible for establishing functional β-cell reserve.
Inserm U693, Le Kremlin-Bicêtre, France;
Julien
J
Auffret
Michael
M
Freemark
Nadège
N
Carré
Yves
Y
Mathieu
Cécile
C
Tourrel-Cuzin
Marc
M
Lombès
Jamileh
J
Movassat
Nadine
N
Binart
D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005260:Female; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000187:drug effects / Q000196:embryology* / Q000254:growth & development; D011247:Pregnancy; D011388:Prolactin / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011981:Receptors, Prolactin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D011981:Receptors, Prolactin; D011388:Prolactin
IGF-II; apoptosis; diabetes; insulin; placental lactogens; proliferation