M. Douglas Benson

Research Interests

• My lab is interested in the molecular mechanisms of craniofacial development and bone healing.  Our studies center on the actions of the Eph family of receptor tyrosine kinases and their membrane-bound ephrin ligands.  These molecules play crucial roles in developmental cell migration and organogenesis throughout the body.
• We recently discovered that ephrin signaling is essential for fusion of the secondary palate, and that it causes palatal epithelial cells to undergo a transition to a motile, mesenchymal phenotype.  We are currently investigating the intracellular signaling and gene expression changes in palatal epithelial cells that cause this transition and thus allow the palate to fuse.  Our studies are important because cleft palate caused by failure of fusion is one of the most common birth defects, and a thorough understanding of the mechanism of fusion will light the way for future medical interventions to treat this devastating condition.
• We and others have also discovered the Ephs and ephrins play a role in the growth and healing of bone.  We are currently investigating the hypothesis that ephrin signaling directs migration of bone stem cells and their differentiation into bone forming osteoblasts and osteocytes.  By manipulating the activity of ephrin signaling pathways in these cells, we hope to one day be able to encourage therapeutic bone growth to treat fractures and osteoporosis.
• Grants Role of ephrins in osteoblast differentiation.  Benson MD (PI); 1 R03 DE020119-01; 2010-2011; $109,875. Ephrin inhibition of regeneration after spinal cord injury.  Benson MD (PI); Christopher and Dana Reeve Foundation; 2011-2012; $150,000.

Teaching Interests

• Teaching responsibilities include: Biochemistry (dental hygiene)

Representative Publications

1. Benson MD, DiBartola SP, Dwulet FE. A unique insertion in the primary structure of bovine amyloid AA protein.  J Lab Clin Med 113:67-72, 1989.
2. Benson MD II, Julien J, Zeldenrust S, Benson MD. A transthyretin variant (alanine 49) associated with familiar amyloidotic polyneuropathy in a French family.  J Med Gen 30:117-119, 1993.
3. Benson MD II, Turpin JC, Lucotte G, Zeldenrust S, LeChevalier B, Benson MD.  A transthyretin variant (alanine 71) associated with familiar amyloidotic polyneuropathy in a French family.  J Med Gen 30:120-122, 1993.
4. Xiao G, Wang D, Benson MD, Karsenty G, Franceschi RT. Role of the alpha 2 integrin in osteoblast-specific gene expression and activation of the Osf2 transcription factor.  J Biol Chem 273:32988-94, 1998.
5. Benson MD*, Aubin JR*, Xiao G, Thomas PE, Franceschi RT.  Cloning of a 2.5 kb murine bone sialoprotein promoter fragment and functional analysis of putative Osf2 binding sites.  J Bone Miner Res 14:396-405, 1999.  * co-first authors
6. Franceschi RT, Xiao G, Jiang D, Thomas PE, Benson MD. Extracellular matrix regulation of osteoblast-specific gene expression: Role of the α2β1integrin and Osf2/Cbfa1 activation.  Proceedings: 6th International Conference on the Chemistry and Biology of Mineralized Tissues, 1999.
7. Xiao G, Jiang D, Thomas PE, Benson MD, Guan K, Karsenty G, Franceschi RT.  MAPK pathways activate and phosphorylate the osteoblast-specific transcription factor Cbfa1.  J Biol Chem 275:4453-4459, 2000.
8. Benson MD, Bargeon JL, Xiao G, Thomas PE, Kim A, Cui Y, Franceschi RT.  Identification of a homeodomain binding element in the bone sialoprotein gene promoter that is required for its osteoblast-selective expression.  J Biol Chem 275:13907-13917, 2000.
9. Xiao G, Gopalakrishnan R, Jiang D, Reith E, Benson MD, Franceschi RT.  Bone morphogenetic proteins, extracellular matrix, and mitogen-activated protein kinase signaling pathways are required for osteoblast-specific gene expression and differentiation in MC3T3-E1 cells.  J Bone Miner Res 17:101-10, 2002.
10. Gopolakrisnan R., Thomas PE, Benson MD, Wang, D, Franceschi RT.  A homeodomain protein element in the bone sialoprotein promoter is critical for tissue-specific expression in bone.  Connect Tiss Res 44 (Suppl. 1): 154-160, 2003.
11. Kuorilehto T, Nissinen M, Koivunen J,  Benson MD, Peltonen J.  NF1 tumor suppressor protein and mRNA in skeletal tissues of developing and adult normal mouse and NF-1 deficient embryos.  J Bone Miner Res 19:983-989, 2004.
12. Benson MD, Romero MI, Lush ME, Lu QR, Henkemeyer M, Parada LF.  Ephrin-B3 is a myelin-based inhibitor of neurite outgrowth.  Proc Natl Acad Sci USA 102(430): 10694-9, 2005.
13. Elefteriou F*, Benson MD*, Sowa H*, Starbuck M, Liu J, Ron D, Parada LF, Karsenty G.  ATF4 mediation of NF1 pathology in bone reveals a nutritional basis for congenital skeletal dysplasias.  Cell Metab 4(6):441-451, 2006 (cover article).  *co-first authors
14. Benson MD, Opperman LA.  Regulation of calvarial bone growth by molecules involved in craniosynostoses.  Monographs in Human Genetics.  Volume 19, Craniosynostoses: Molecular Genetics, Principles of Diagnosis and Treatment.  Muenke M, Kress W, Collmann H, Solomon BD, eds., S. Karger, A.G., 2011.
15. San Miguel S, Serrano MJ, Sachar A, Henkemeyer M, Svoboda KK, Benson MD.  Ephrin reverse signaling controls palate fusion via a Pl3 kinase-dependent mechanism.  Dev Dyn 240:357-364, 2011.
16. Benson MD,  Serrano MJ.  Ephrin regulation of palate development.  Front Physiol 3:376, 2012.
17. Sachar A, Strom TA, Serrano MJ, Benson MD, Opperman LA, Svoboda KK, Liu X.  Osteoblasts responses to three-dimensional nanofibrous gelatin scaffolds.  J Biomed Mater Res A 100:3029-41, 2012.
18. Benson MD, Opperman L, Westerlund J, Fernandez C, San Miguel S, Henkemeyer M, Chenaux G. Ephrin B stimulation of calvarial bone growth.  Dev Dyn 241:1901-1910, 2012.
19. Logan SM, Romero MI, Nguyen DH, Benson MD.  Ephrin-B2 expression in the proprioceptive sensory system.  Neurosci Lett 545:69-74, 2013.
20. Serrano MJ, Liu J, Svoboda KK, Nawshad A, Benson MD.  Ephrin reverse signaling mediates palatal fusion and epithelial-to-mesenchymal transition independently of TgfΒ3.  Journal of Cellular Physiology 230(12): 2961-72, 2015.
21. Hozhabri MS, Benson MD, Vu MD, Patel RH, Martinez RM, Nakhaie FN, Kim HK, Varanasi VG.  Decreasing NF-_kB expression enhances odontoblastic differentiation and collagen expression in dental pulp stem cells exposed to inflammatory cytokines. PLoS One 10:30113334.