Neuropilin-2 promotes branching morphogenesis in the mouse mammary gland
- 15 July 2011
- journal article
- Published by The Company of Biologists in Development
- Vol. 138 (14), 2969-2976
- https://doi.org/10.1242/dev.051318
Abstract
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;NRP2loxP/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 VEGF165, 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;NRP2loxP/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.This publication has 45 references indexed in Scilit:
- Vascular Endothelial Growth Factor Induces Branching Morphogenesis/Tubulogenesis in Renal Epithelial Cells in a Neuropilin-Dependent FashionMolecular and Cellular Biology, 2005
- The Fallacy of Epithelial Mesenchymal Transition in NeoplasiaCancer Research, 2005
- Interactions of Multiple Heparin Binding Growth Factors with Neuropilin-1 and Potentiation of the Activity of Fibroblast Growth Factor-2Online Journal of Public Health Informatics, 2005
- Residues within the First Subdomain of the FERM-like Domain in Focal Adhesion Kinase Are Important in Its RegulationOnline Journal of Public Health Informatics, 2005
- Roles of Neuropilins in Neuronal Development, Angiogenesis, and CancersWorld Journal of Surgery, 2005
- A peptide corresponding to the neuropilin-1-binding site on VEGF165 induces apoptosis of neuropilin-1-expressing breast tumour cellsBritish Journal of Cancer, 2005
- Semaphorin 3B (SEMA3B) induces apoptosis in lung and breast cancer, whereas VEGF 165 antagonizes this effectProceedings of the National Academy of Sciences of the United States of America, 2004
- Neuropilin-1 Is Expressed by Endothelial and Tumor Cells as an Isoform-Specific Receptor for Vascular Endothelial Growth FactorCell, 1998
- Cre-mediated gene deletion in the mammary glandNucleic Acids Research, 1997
- Neuropilin Is a Receptor for the Axonal Chemorepellent Semaphorin IIICell, 1997