Molecular Cell & Developmental Biology
225 Sinsheimer Laboratories
Phone: 831.459.4986
Fax: 831.459.3139
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LINDSAY HINCK Associate Professor of MCD Biology B.S., Western Washington University M.S., UC, Davis Ph.D., Stanford University Post doctorate, UC San Francisco HINCK LAB

225 Sinsheimer Laboratories University of California Santa Cruz, CA 95064 phone 831.459.5253 fax 831.459.3139 hinck@biology.ucsc.edu office hours

Project I: Neural Development

A central question in developmental neurobiology is how neurons and their axons migrate in response to a variety of attractive and repellent guidance cues. Often, an axon follows a complicated trajectory using multiple guidance cues en route to its final destination. Netrin1 is an example of such a cue and it is bifunctional, either attracting or repelling axons depending on the expression of cell surface receptors. Two vertebrate families of Netrin1 receptors have been identified: the Deleted in Colorectal Cancer (DCC) family, comprising DCC and Neogenin1; and the UNC5 family, comprising UNC5A-D. The DCC family mediates attraction to Netrin1 while the UNC5 family mediates repulsion by forming a Netrin1 dependent complex with DCC.

We have focused on understanding Netrin1 signaling as it is mediated directly through its repellent UNC5 receptors. We identified a number of candidate signal transduction proteins in a yeast two-hybrid screen. One candidate is PICK1 (Protein Interacting with C Kinase 1), a PDZ protein that acts as an adaptor for PKCa. Using a variety of protein trafficking assays, we discovered that phosphorylation of UNC5A by PKCa results in its selective endocytotic internalization, leaving DCC on the cell surface. When this occurs in a Netrin1 gradient, a repulsive response is converted to attraction. Currently, we are investigating how growth cones are steered using this mechanism by identifying the signals that activate PKCa.

A second candidate identified in our yeast two-hybrid screen is MAGE-D1 (NRAGE), a pro-apoptotic signaling protein. We have shown that it regulates neural number during spinal cord development by mediating UNC5A-induced cell death of spinal accessory motoneurons. Characterization of Mage-d1 knock-out mice are underway as we further investigate how this apoptotic signaling pathway sculpts the developing nervous system.

Project II: Mammary Gland Development

“Axon” guidance cues were discovered in the developing nervous system, but research in my laboratory and others has shown that these cues are versatile, functioning in many different tissues and organs. We have investigated the role of Netrin and Slit families of guidance cues in the developing breast (mammary gland), a tree-like, bi-layered structure composed of an outer layer of myoepithelial cells and an inner layer of luminal epithelial cells. We discovered that Netrin1 and Slit2 are expressed throughout the breast, but expression of their receptors Neogenin1 and Robo1, respectively, are restricted to the outer layer of myoepithelial cells. Loss of any one of the genes encoding these proteins results in modest tissue disorganization, but compound loss of both Netrin1 and Slit2 leads to generalized loss of adhesion between myoepithelial and luminal epithelial cell layers. These results establish a new function for Netrins and Slits in generating adhesive contacts between layers of epithelium during organ morphogenesis. We are currently elucidating the signaling pathways mediated by Robo1 receptors in myoepithelial cells, and investigating a role for Slits as breast tumor suppressor genes.

Selected Publications
*Williams M.E., *Lu, X., *McKenna, W., Boyette, A., Washington, R., Tessier-Lavigne, M., Hinck, L. UNC5A promotes neuronal apoptosis during spinal cord development independent of netrin-1. Nature Neuroscience, 2006: 9(8): 996-998.

*Bartoe, J., *McKenna, W., Quan, T., Stafford, B., Moore, J. A. Xia, J., Takamiya, K., Huganir, R.L., Hinck, L.  PICK1/PKC-mediated endocytosis converts netrin-mediated repulsion to attraction. Journal of Neuroscience, 2006: 26(12): 3192-205.

*Strickland P., *Shin G., Plump A., Tessier-Lavigne M., Hinck L., Slit2 and Netrin1 act synergistically as adhesive cues to generate tubular bi-layers during ductal morphogenesis. Development, 2006: 133(5): 823-32.

*Williams M. E., *Wu C.-Y., *McKenna W., Hinck, L.  Surface expression of the netrin receptor UNC5H1 is regulated through a PICK1/PKC-dependent mechanism.  J. Neuroscience 2003: 23(36): 11279-11288.

Williams, M.E., Strickland, P., Watanabe, K. and Hinck, L. UNC5H1 induces apoptosis via its juxtamembrane region through an interaction with NRAGE. Journal of Biological Chemistry, 2003: 278(19): 17483-90.

*Srinivasan, K., *Strickland, P., Valdes, A., Shin, G.C. and Hinck, L. Netrin-1.neogenin interaction stabilizes multipotent progenitor cap cells during mammary gland development. Developmental Cell, 2003: 4; 1-20.

*Hong, K., *Hinck, L., Nishiyama, M., Poo, M-m., Tessier-Lavigne, M. and *Stein, E. A ligand-gated association between cytoplasmic domains of UNC5 and DCC family receptors converts netrin-induced growth cone attraction to repulsion. Cell, 1999: 97: 927-41.

*Leonardo, E.D., *Hinck, L., *Masu, M., Keino-Masu, K., Ackerman, S. L. and Tessier-Lavigne, M. Vertebrate homologues of C. elegans UNC-5 are candidate netrin receptors. Nature, 1997: 386: 833-838.

Keino-Masu, K., Masu, M., Hinck, L., Leonardo, E.D., Chan, S. S-Y., Culotti, J. and Tessier-Lavigne, M. Deleted in colorectal carcinoma (DCC) encodes a netrin receptor. Cell, 1996: 87: 175-185.

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*denotes equal contribution