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Sarah Knox Ph.D.

Organogenesis and Regeneration using the salivary gland

Sarah Knox Ph.D.

My goal is to investigate how neuronal-epithelial interactions control organogenesis and regeneration. My work primarily utilizes the mouse embryonic submandibular gland ex vivo model system to examine the role of the parasympathetic ganglion in epithelial branching morphogenesis and regeneration.

The submandibular gland has an autonomic ganglion located in and around the glandular epithelium from the earliest stages of development, and remains with the gland after dissection for ex vivo organ culture. This makes the salivary gland an exceptional model for understanding the influence of the peripheral nervous system on organogenesis and repair processes. During my post-doctorate I discovered that the parasympathetic ganglion plays a critical role in submandibular gland morphogenesis by maintaining keratin 5+ epithelial stem/progenitor cells through an acetylcholine /muscarinic/epidermal growth factor receptor pathway. In addition, I found this pathway maintains progenitor cells in the developing prostate and the adult submandibular gland. More recently I have also established that the neurotrophic factor neurturin secreted by the submandibular gland epithelium is required for parasympathetic ganglion function and survival, and increases organ regeneration after injury. Current projects examine 1) the regulation of stem cell factors by the nervous system during development and regeneration; 2) understanding how stem cells and the nerves are influenced by therapeutic radiation and disease; and 3) how neurotransmitters regulate epithelial architecture and stem cell movement during organogenesis. To investigate these processes we use a combination of genetic, high resolution microscopy and biochemical approaches with the aim of correlating our findings with human tissue.

Selected Publications:

Knox, S. M, Melrose, J., and Whitelock, J. (2001). Electrophoretic, Biosensor and bioactivity analysis of perlecans of different cellular origins. Proteomics 1 (12): 1534-41. PMID: 11747213

Knox, S. M., Merry, C., Stringer, S., Melrose, J., and Whitelock, J.M. (2002). Not all perlecans are created equal: interactions with fibroblast growth factor (FGF) 2 and FGF receptors. Journal of Biological Chemistry 277 (17): 14657-14665. PMID: 11847221

Melrose, J., Smith, S., Knox, S. M., and Whitelock, J. (2002). Perlecan, the multidomain HS-proteoglycan of basement membranes is a prominent pericellular component of ovine hypertrophic vertebral growth plate and cartilaginous endplate chondrocytes. Histochemistry and cell biology 118 (4): 269-280. PMID: 12376823

Kang, S., Feinlab, J., Knox, S. M., Ketteringham, M., and Krauss, R. (2003). Promyogenic members of the Ig and cadherin families associate to positively regulate differentiation. Proceedings of the National Academy of Sciences of the United States of America 100(7): 3989-3994. PMCID: PMC153035

Knox, S. M., Fosang, A., Last, K., Melrose, J., and Whitelock, J.M. (2005). Perlecan from epithelial cells is a hybrid heparin/chondroitin/keratin sulfate proteoglycan. FEBS Letters 579 (22): 5019-23. PMID:16129435

Melrose, J., Roughley, P., Knox, S. M., Smith, S., Lord, M. and Whitelock J. (2006). The structure, location, and function of perlecan, a prominent pericellular proteoglycan of fetal, postnatal, and mature hyaline cartilages. Journal of Biological Chemistry 281(48): 36905-36914. PMID: 16984910

Kirkpatrick, C., Knox, S. M., Staaz, W., Fox, B., Lercher, D., and Selleck, S. (2006). The function of a Drosophila glypican does not depend entirely on heparan sulfate modification. Developmental Biology 300(2): 570-582. PMID: 17055473

Knox, S.M, Ge, H., Ren, Y., Dimitroff, B., Howe, K., Arsham, A., Easterday, M., Neufeld, T., O’Connor, M., and Scott B. Selleck. (2007). Mechanisms of TSC-mediated Control of Synapse Assembly and Axon Guidance. PLoS ONE. 2:e375. PMCID:PMC1847706

Patel, V.N., Knox, S.M., Likar, K. M., Lathrop, C.A., Hossain, R., Eftekhari, S., Elkins, M., Vlodasky, I., Whitelock, J. M., and Hoffman, M. P. (2007). Heparanase cleavage of perlecan heparan sulfate modulates FGF10 activity during ex vivo submandibular gland branching morphogenesis. Development 134:4177-86. PMID: 17959718

Whitelock, J., Ma, JL., Davies, N., Nielsen, N., Chuang, C., Rees, M., Iozzo, RV., Knox, S., Lord, M. (2008). Recombinant heparan sulfate for use in tissue engineering applications. J Chem Tech Biotech. 83(4):496-504.