Netrin-1/neogenin interaction stabilizes multipotent progenitor cap cells during mammary gland morphogenesis.
Netrin-1 and its receptors play an essential role patterning the nervous system by guiding neurons and axons to their targets. To explore whether netrin-1 organizes nonneural tissues, we examined its role in mammary gland morphogenesis. Netrin-1 is expressed in prelumenal cells, and its receptor neogenin is expressed in a complementary pattern in adjacent cap cells of terminal end buds (TEBs). We discovered that loss of either gene results in disorganized TEBs characterized by exaggerated subcapsular spaces, breaks in basal lamina, dissociated cap cells, and an increased influx of cap cells into the prelumenal compartment. Cell aggregation assays demonstrate that neogenin mediates netrin-1-dependent cell clustering. Thus, netrin-1 appears to act locally through neogenin to stabilize the multipotent progenitor (cap) cell layer during mammary gland development. Our results suggest that netrin-1 and its receptor neogenin provide an adhesive, rather than a guidance, function during nonneural organogenesis.
Srinivasan
Karpagam
K
Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
Strickland
Phyllis
P
Valdes
Ana
A
Shin
Grace C
GC
Hinck
Lindsay
L
D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001485:Basement Membrane / Q000378:metabolism / Q000648:ultrastructure; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics*; D002450:Cell Communication / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D007797:Laminin / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000002:abnormalities* / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism; D009414:Nerve Growth Factors / Q000172:deficiency* / Q000235:genetics; D000075388:Netrin-1; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
D000199:Actins; D015820:Cadherins; D007797:Laminin; D008565:Membrane Proteins; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D025521:Tumor Suppressor Proteins; C091279:neogenin; D000075388:Netrin-1