Netrin-1 can affect morphogenesis and differentiation of the mouse mammary gland.
Netrin-1 has been shown to regulate the function of the EGF-like protein Cripto-1 (Cr-1) and affect mammary gland development. Since Cr-1 is a target gene of Nanog and Oct4, we investigated the relationship between Netrin-1 and Cr-1, Nanog and Oct4 during different stages of development in the mouse mammary gland. Results from histological analysis show that exogenous Netrin-1 was able to induce formation of alveolar-like structures within the mammary gland terminal end buds of virgin transgenic Cripto-1 mice and enhance mammary gland alveologenesis in early pregnant FVB/N mice. Results from immunostaining and Western blot analysis show that Netrin-1, Nanog and Oct4 are expressed in the mouse embryonic mammary anlage epithelium while Cripto-1 is predominantly expressed outside this structure in the surrounding mesenchyme. We find that in lactating mammary glands of postnatal FVB/N mice, Netrin-1 expression is highest while Cripto-1 and Nanog levels are lowest indicating that Netrin-1 may perform a role in the mammary gland during lactation. HC-11 mouse mammary epithelial cells stimulated with lactogenic hormones and exogenous soluble Netrin-1 showed increased beta-casein expression as compared to control thus supporting the potential role for Netrin-1 during functional differentiation of mouse mammary epithelial cells. Finally, mouse ES cells treated with exogenous soluble Netrin-1 showed reduced levels of Nanog and Cripto-1 and higher levels of beta-III tubulin during differentiation. These results suggest that Netrin-1 may facilitate functional differentiation of mammary epithelial cells and possibly affect the expression of Nanog and/or Cripto-1 in multipotent cells that may reside in the mammary gland.
Strizzi
Luigi
L
Mammary Biology and Tumorigenesis Laboratory, National Cancer Institute, Bethesda, Maryland 20892, USA.
Mancino
Mario
M
Bianco
Caterina
C
Raafat
Ahmed
A
Gonzales
Monica
M
Booth
Brian W
BW
Watanabe
Kazuhide
K
Nagaoka
Tadahiro
T
Mack
David L
DL
Howard
Beatrice
B
Callahan
Robert
R
Smith
Gilbert H
GH
Salomon
David S
DS
D000818:Animals; D002364:Caseins / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D003907:Dexamethasone / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005938:Glucocorticoids / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007774:Lactation; D008297:Male; D008321:Mammary Glands, Animal / Q000033:anatomy & histology / Q000254:growth & development* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis / Q000502:physiology*; D000071317:Nanog Homeobox Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D000075388:Netrin-1; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011388:Prolactin / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D002364:Caseins; D005938:Glucocorticoids; D018398:Homeodomain Proteins; D007328:Insulin; D008562:Membrane Glycoproteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D009363:Neoplasm Proteins; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; C489450:Tdgf1 protein, mouse; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; D004815:Epidermal Growth Factor; D003907:Dexamethasone; D011388:Prolactin