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Signal transducer and activator of transcription (Stat) 5 controls the proliferation and differentiation of mammary alveolar epithelium.

Miyoshi K, Shillingford JM, Smith GH, Grimm SL, Wagner KU, Oka T, Rosen JM, Robinson GW, Hennighausen L - J. Cell Biol. (2001)

Bottom Line: Stat5- mammary epithelium developed ducts but failed to form alveoli, and no milk protein gene expression was observed.Expression of NKCC1, an Na-K-Cl cotransporter characteristic for ductal epithelia, and ZO-1, a protein associated with tight junction, were maintained in the alveoli-like structures of PrlR- and Stat5- epithelia.In contrast, the Na-Pi cotransporter Npt2b, and the gap junction component connexin 32, usually expressed in secretory epithelia, were undetectable in PrlR- and Stat5- mice.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. mammary@nih.gov

ABSTRACT
Functional development of mammary epithelium during pregnancy depends on prolactin signaling. However, the underlying molecular and cellular events are not fully understood. We examined the specific contributions of the prolactin receptor (PrlR) and the signal transducers and activators of transcription 5a and 5b (referred to as Stat5) in the formation and differentiation of mammary alveolar epithelium. PrlR- and Stat5- mammary epithelia were transplanted into wild-type hosts, and pregnancy-mediated development was investigated at a histological and molecular level. Stat5- mammary epithelium developed ducts but failed to form alveoli, and no milk protein gene expression was observed. In contrast, PrlR- epithelium formed alveoli-like structures with small open lumina. Electron microscopy revealed undifferentiated features of organelles and a perturbation of cell-cell contacts in PrlR- and Stat5- epithelia. Expression of NKCC1, an Na-K-Cl cotransporter characteristic for ductal epithelia, and ZO-1, a protein associated with tight junction, were maintained in the alveoli-like structures of PrlR- and Stat5- epithelia. In contrast, the Na-Pi cotransporter Npt2b, and the gap junction component connexin 32, usually expressed in secretory epithelia, were undetectable in PrlR- and Stat5- mice. These data demonstrate that signaling via the PrlR and Stat5 is critical for the proliferation and differentiation of mammary alveoli during pregnancy.

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Npt2b expression was not detected in PrlR- and Stat5- alveoli-like structures at parturition. Immunohistochemical staining of Npt2b (red) and E-cadherin (green) in mammary epithelia of virgin mice (A, C, and E) and after parturition (B, D, and F). Npt2b was detected in apical membranes of secreting epithelia from wild-type tissue (B, white arrow). PrlR- and Stat5- epithelia at parturition did not contain Npt2b (D and F). E-cadherin was detected in the sub-apical/basolateral membrane of all samples (A–F). (G) Wild-type epithelia at pregnancy day 12 did not express Npt2b. Du, duct.
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fig7: Npt2b expression was not detected in PrlR- and Stat5- alveoli-like structures at parturition. Immunohistochemical staining of Npt2b (red) and E-cadherin (green) in mammary epithelia of virgin mice (A, C, and E) and after parturition (B, D, and F). Npt2b was detected in apical membranes of secreting epithelia from wild-type tissue (B, white arrow). PrlR- and Stat5- epithelia at parturition did not contain Npt2b (D and F). E-cadherin was detected in the sub-apical/basolateral membrane of all samples (A–F). (G) Wild-type epithelia at pregnancy day 12 did not express Npt2b. Du, duct.

Mentions: To further examine the cell adhesion defect apparent in Stat5- epithelial cells, we investigated the expression of additional molecules involved in cell adhesion. Cadherins mediate cell–cell adhesion and also contribute to the maintenance of apical–basal polarity (Tepass et al., 2000). Indeed, E-cadherin has been shown to play a role in the morphogenesis and growth of the mammary gland (Daniel et al., 1995; Delmas et al., 1999). On this basis, we hypothesized that E-cadherin expression might be altered in Stat5- mammary epithelial cells and thus contribute to the observed alterations in cell adhesion. However, E-cadherin expression along cell–cell borders did not appear to be significantly perturbed when comparing Stat5- and wild-type epithelia (Figs. 5 and 7).


Signal transducer and activator of transcription (Stat) 5 controls the proliferation and differentiation of mammary alveolar epithelium.

Miyoshi K, Shillingford JM, Smith GH, Grimm SL, Wagner KU, Oka T, Rosen JM, Robinson GW, Hennighausen L - J. Cell Biol. (2001)

Npt2b expression was not detected in PrlR- and Stat5- alveoli-like structures at parturition. Immunohistochemical staining of Npt2b (red) and E-cadherin (green) in mammary epithelia of virgin mice (A, C, and E) and after parturition (B, D, and F). Npt2b was detected in apical membranes of secreting epithelia from wild-type tissue (B, white arrow). PrlR- and Stat5- epithelia at parturition did not contain Npt2b (D and F). E-cadherin was detected in the sub-apical/basolateral membrane of all samples (A–F). (G) Wild-type epithelia at pregnancy day 12 did not express Npt2b. Du, duct.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2198867&req=5

fig7: Npt2b expression was not detected in PrlR- and Stat5- alveoli-like structures at parturition. Immunohistochemical staining of Npt2b (red) and E-cadherin (green) in mammary epithelia of virgin mice (A, C, and E) and after parturition (B, D, and F). Npt2b was detected in apical membranes of secreting epithelia from wild-type tissue (B, white arrow). PrlR- and Stat5- epithelia at parturition did not contain Npt2b (D and F). E-cadherin was detected in the sub-apical/basolateral membrane of all samples (A–F). (G) Wild-type epithelia at pregnancy day 12 did not express Npt2b. Du, duct.
Mentions: To further examine the cell adhesion defect apparent in Stat5- epithelial cells, we investigated the expression of additional molecules involved in cell adhesion. Cadherins mediate cell–cell adhesion and also contribute to the maintenance of apical–basal polarity (Tepass et al., 2000). Indeed, E-cadherin has been shown to play a role in the morphogenesis and growth of the mammary gland (Daniel et al., 1995; Delmas et al., 1999). On this basis, we hypothesized that E-cadherin expression might be altered in Stat5- mammary epithelial cells and thus contribute to the observed alterations in cell adhesion. However, E-cadherin expression along cell–cell borders did not appear to be significantly perturbed when comparing Stat5- and wild-type epithelia (Figs. 5 and 7).

Bottom Line: Stat5- mammary epithelium developed ducts but failed to form alveoli, and no milk protein gene expression was observed.Expression of NKCC1, an Na-K-Cl cotransporter characteristic for ductal epithelia, and ZO-1, a protein associated with tight junction, were maintained in the alveoli-like structures of PrlR- and Stat5- epithelia.In contrast, the Na-Pi cotransporter Npt2b, and the gap junction component connexin 32, usually expressed in secretory epithelia, were undetectable in PrlR- and Stat5- mice.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. mammary@nih.gov

ABSTRACT
Functional development of mammary epithelium during pregnancy depends on prolactin signaling. However, the underlying molecular and cellular events are not fully understood. We examined the specific contributions of the prolactin receptor (PrlR) and the signal transducers and activators of transcription 5a and 5b (referred to as Stat5) in the formation and differentiation of mammary alveolar epithelium. PrlR- and Stat5- mammary epithelia were transplanted into wild-type hosts, and pregnancy-mediated development was investigated at a histological and molecular level. Stat5- mammary epithelium developed ducts but failed to form alveoli, and no milk protein gene expression was observed. In contrast, PrlR- epithelium formed alveoli-like structures with small open lumina. Electron microscopy revealed undifferentiated features of organelles and a perturbation of cell-cell contacts in PrlR- and Stat5- epithelia. Expression of NKCC1, an Na-K-Cl cotransporter characteristic for ductal epithelia, and ZO-1, a protein associated with tight junction, were maintained in the alveoli-like structures of PrlR- and Stat5- epithelia. In contrast, the Na-Pi cotransporter Npt2b, and the gap junction component connexin 32, usually expressed in secretory epithelia, were undetectable in PrlR- and Stat5- mice. These data demonstrate that signaling via the PrlR and Stat5 is critical for the proliferation and differentiation of mammary alveoli during pregnancy.

Show MeSH
Related in: MedlinePlus