Neuropilin-2 promotes branching morphogenesis in the mouse mammary gland
UMass Chan Affiliations
Department of Cancer BiologyDocument Type
Journal ArticlePublication Date
2011-07-15Keywords
AnimalsCells, Cultured
Epithelial Cells
Female
Focal Adhesion Protein-Tyrosine Kinases
Gene Expression Regulation, Developmental
Immunoblotting
Immunohistochemistry
Mammary Glands, Animal
Mice
Mice, Knockout
Morphogenesis
Neuropilin-2
RNA Interference
Reverse Transcriptase Polymerase Chain Reaction
Vascular Endothelial Growth Factor A
Amino Acids, Peptides, and Proteins
Animal Experimentation and Research
Body Regions
Cancer Biology
Neoplasms
Metadata
Show full item recordAbstract
Although the neuropilins were characterized as semaphorin receptors that regulate axon guidance, they also function as vascular endothelial growth factor (VEGF) receptors and contribute to the development of other tissues. Here, we assessed the role of NRP2 in mouse mammary gland development based on our observation that NRP2 is expressed preferentially in the terminal end buds of developing glands. A floxed NRP2 mouse was bred with an MMTV-Cre strain to generate a mammary gland-specific knockout of NRP2. MMTV-Cre;NRP2(loxP/loxP) mice exhibited significant defects in branching morphogenesis and ductal outgrowth compared with either littermate MMTV-Cre;NRP2(+/loxP) or MMTV-Cre mice. Mechanistic insight into this morphological defect was obtained from a mouse mammary cell line in which we observed that VEGF(165), an NRP2 ligand, induces branching morphogenesis in 3D cultures and that branching is dependent upon NRP2 as shown using shRNAs and a function-blocking antibody. Epithelial cells in the mouse mammary gland express VEGF, supporting the hypothesis that this NRP2 ligand contributes to mammary gland morphogenesis. Importantly, we demonstrate that VEGF and NRP2 activate focal adhesion kinase (FAK) and promote FAK-dependent branching morphogenesis in vitro. The significance of this mechanism is substantiated by our finding that FAK activation is diminished significantly in developing MMTV-Cre;NRP2(loxP/loxP) mammary glands compared with control glands. Together, our data reveal a VEGF/NRP2/FAK signaling axis that is important for branching morphogenesis and mammary gland development. In a broader context, our data support an emerging hypothesis that directional outgrowth and branching morphogenesis in a variety of tissues are influenced by signals that were identified initially for their role in axon guidance.Source
Development. 2011 Jul;138(14):2969-76. doi:10.1242/dev.051318 Link to article on publisher's site
DOI
10.1242/dev.051318Permanent Link to this Item
http://hdl.handle.net/20.500.14038/26299PubMed ID
21693513Related Resources
Rights
Publisher PDF posted as allowed by the publisher's author rights policy at http://dev.biologists.org/site/misc/rights_permissions.xhtml#author
ae974a485f413a2113503eed53cd6c53
10.1242/dev.051318