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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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Pregnancy-mediated mammary gland development depends on the PrlR and Stat5. (A) Whole mount analyses of wild-type, PrlR-, and Stat5- mammary epithelia at parturition. The lower panel represents a higher magnification. Wild-type epithelium filled the fat pad and developed lobuloalveolar structures (*). PrlR- and Stat5- mammary epithelia were severely underdeveloped. PrlR- epithelium exhibited wide ducts (black arrow), short branches, and few alveoli-like structures. Stat5- epithelium displayed normal branches with small decorations (black arrowhead). (B) Histological sections of the whole mounts shown in A. The lower panel represents a 6× higher magnification. Wild-type epithelium was fully expanded, filled the fat pad and alveolar lumina contained milk (*). However, all  epithelia were sparse, and the alveoli-like structures (black arrowhead) did not contain milk. The epithelial cells are cuboidal in shape (white arrow). Note the presence of open lumina in the alveoli-like structures in PrlR-, but not Stat5- epithelium. (C) Whole mount analyses of wild-type and PrlR- and Stat5- virgin mammary epithelia 8 wk after transplantation. All transplanted epithelia completely filled the fat pad.
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fig1: Pregnancy-mediated mammary gland development depends on the PrlR and Stat5. (A) Whole mount analyses of wild-type, PrlR-, and Stat5- mammary epithelia at parturition. The lower panel represents a higher magnification. Wild-type epithelium filled the fat pad and developed lobuloalveolar structures (*). PrlR- and Stat5- mammary epithelia were severely underdeveloped. PrlR- epithelium exhibited wide ducts (black arrow), short branches, and few alveoli-like structures. Stat5- epithelium displayed normal branches with small decorations (black arrowhead). (B) Histological sections of the whole mounts shown in A. The lower panel represents a 6× higher magnification. Wild-type epithelium was fully expanded, filled the fat pad and alveolar lumina contained milk (*). However, all epithelia were sparse, and the alveoli-like structures (black arrowhead) did not contain milk. The epithelial cells are cuboidal in shape (white arrow). Note the presence of open lumina in the alveoli-like structures in PrlR-, but not Stat5- epithelium. (C) Whole mount analyses of wild-type and PrlR- and Stat5- virgin mammary epithelia 8 wk after transplantation. All transplanted epithelia completely filled the fat pad.

Mentions: Although the PrlR is required for development of mammary epithelium during pregnancy (Ormandy et al., 1997b), the contribution of Stat5 in this process is not known. Stat5 is downstream of the PrlR, and it can be hypothesized that the loss of either signaling component might lead to a comparable phenotype. To investigate this, we compared the pregnancy-induced development of PrlR- and Stat5- epithelia. Because Stat5- and PrlR- mice are infertile, mammary epithelia from mature virgins was transplanted into the cleared fat pad of recipients to expose these epithelia to pregnancy hormones. Whole mount analyses demonstrated that ductal development during puberty was not affected in PrlR- and Stat5- mice (Fig. 1 C). In contrast, pregnancy-mediated alveolar development was severely impaired (Fig. 1 A). Whereas wild-type ducts were decorated with expanded alveoli, the epithelium was greatly reduced in Stat5- transplants and did not have the appearance of true lobulo-alveolar units. Histological sections demonstrated that the majority of Stat5- alveoli-like structures did not have lumina (Fig. 1 B, right panel). Furthermore, individual Stat5- epithelial cells exhibited abnormal columnar shapes and the epithelial architecture appeared disorganized (Fig. 1 B, right panel, white arrow). On the other hand, small open lumina were evident in the more organized alveoli-like structures in the PrlR- transplants (Fig. 1 B, middle panel). To further evaluate the differences between Stat5- and PrlR- alveoli-like structures, we analyzed serial sections. Whereas PrlR- tissue exhibited consistently open lumina, they were not apparent in Stat5- tissue (unpublished data).


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)

Pregnancy-mediated mammary gland development depends on the PrlR and Stat5. (A) Whole mount analyses of wild-type, PrlR-, and Stat5- mammary epithelia at parturition. The lower panel represents a higher magnification. Wild-type epithelium filled the fat pad and developed lobuloalveolar structures (*). PrlR- and Stat5- mammary epithelia were severely underdeveloped. PrlR- epithelium exhibited wide ducts (black arrow), short branches, and few alveoli-like structures. Stat5- epithelium displayed normal branches with small decorations (black arrowhead). (B) Histological sections of the whole mounts shown in A. The lower panel represents a 6× higher magnification. Wild-type epithelium was fully expanded, filled the fat pad and alveolar lumina contained milk (*). However, all  epithelia were sparse, and the alveoli-like structures (black arrowhead) did not contain milk. The epithelial cells are cuboidal in shape (white arrow). Note the presence of open lumina in the alveoli-like structures in PrlR-, but not Stat5- epithelium. (C) Whole mount analyses of wild-type and PrlR- and Stat5- virgin mammary epithelia 8 wk after transplantation. All transplanted epithelia completely filled the fat pad.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2198867&req=5

fig1: Pregnancy-mediated mammary gland development depends on the PrlR and Stat5. (A) Whole mount analyses of wild-type, PrlR-, and Stat5- mammary epithelia at parturition. The lower panel represents a higher magnification. Wild-type epithelium filled the fat pad and developed lobuloalveolar structures (*). PrlR- and Stat5- mammary epithelia were severely underdeveloped. PrlR- epithelium exhibited wide ducts (black arrow), short branches, and few alveoli-like structures. Stat5- epithelium displayed normal branches with small decorations (black arrowhead). (B) Histological sections of the whole mounts shown in A. The lower panel represents a 6× higher magnification. Wild-type epithelium was fully expanded, filled the fat pad and alveolar lumina contained milk (*). However, all epithelia were sparse, and the alveoli-like structures (black arrowhead) did not contain milk. The epithelial cells are cuboidal in shape (white arrow). Note the presence of open lumina in the alveoli-like structures in PrlR-, but not Stat5- epithelium. (C) Whole mount analyses of wild-type and PrlR- and Stat5- virgin mammary epithelia 8 wk after transplantation. All transplanted epithelia completely filled the fat pad.
Mentions: Although the PrlR is required for development of mammary epithelium during pregnancy (Ormandy et al., 1997b), the contribution of Stat5 in this process is not known. Stat5 is downstream of the PrlR, and it can be hypothesized that the loss of either signaling component might lead to a comparable phenotype. To investigate this, we compared the pregnancy-induced development of PrlR- and Stat5- epithelia. Because Stat5- and PrlR- mice are infertile, mammary epithelia from mature virgins was transplanted into the cleared fat pad of recipients to expose these epithelia to pregnancy hormones. Whole mount analyses demonstrated that ductal development during puberty was not affected in PrlR- and Stat5- mice (Fig. 1 C). In contrast, pregnancy-mediated alveolar development was severely impaired (Fig. 1 A). Whereas wild-type ducts were decorated with expanded alveoli, the epithelium was greatly reduced in Stat5- transplants and did not have the appearance of true lobulo-alveolar units. Histological sections demonstrated that the majority of Stat5- alveoli-like structures did not have lumina (Fig. 1 B, right panel). Furthermore, individual Stat5- epithelial cells exhibited abnormal columnar shapes and the epithelial architecture appeared disorganized (Fig. 1 B, right panel, white arrow). On the other hand, small open lumina were evident in the more organized alveoli-like structures in the PrlR- transplants (Fig. 1 B, middle panel). To further evaluate the differences between Stat5- and PrlR- alveoli-like structures, we analyzed serial sections. Whereas PrlR- tissue exhibited consistently open lumina, they were not apparent in Stat5- tissue (unpublished data).

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