NEUROTROPHIN RECEPTOR-INTERACTING MELANOMA-ASSOCIATED ANTIGEN PROTEIN ACTIVATES NUCLEAR FACTOR KAPPA BETA REPRESSING BONE MORPHOGENIC PROTEIN INDUCED APOPTOSIS THROUGH MACROPHAGE MIGRATION INHIBITORY FACTOR EXPRESSION

NEUROTROPHIN RECEPTOR-INTERACTING MELANOMA-ASSOCIATED ANTIGEN PROTEIN ACTIVATES NUCLEAR FACTOR KAPPA BETA REPRESSING BONE MORPHOGENIC PROTEIN INDUCED APOPTOSIS THROUGH MACROPHAGE MIGRATION INHIBITORY FACTOR EXPRESSION 

By Nicholas N Matluk III

Thesis Advisor:  Dr. Joseph Verdi

A Lay Abstract of the Thesis Presented in Partial Fulfillment of the

Requirements for the Degree of Master of Science

(in Biochemistry)

December 2011

Keywords:  NRAGE, MIF, BMP, Apoptosis, Stem cells

From eliminating transitory organs to tissue remodeling, apoptosis programmed cell death, or apoptosis is a critical step in embryogenesis and the development of an organism.  On embryonic day thirteen of life in the mouse, neural progenitor cells undergo apoptosis, thus limiting the number of stem cells that can proliferate and differentiate into the nervous system.  While previous research has shown that this this process is highly regulated by the Bone Morphogenic Protein Pathway (BMP Pathway), we believed that this pathway also contained a contrasting anti-apoptotic portion.  In this thesis, we show that activation of the BMP pathway resulted in the dramatic increase in expression of the anti-apoptotic cytokine, macrophage migration inhibitory factor (MIF), which counteracted BMP driven apoptosis.  Neural stem cells from mif knockout mice, when stimulated with BMP had a higher predisposition for apoptosis.  When given as a therapeutic agent, recombinant MIF could counteract this increase in apoptosis.  Given our research, it could be seen that the increase in apoptosis in E13 cortical progenitors when MIF is not properly expressed could have lasting detrimental effects on the adult neural stem cell population.  A reduced population of neural stem cells could result in a slower recovery or a poorer prognosis after neural injury, since endogenous neural stem cells can replenish damaged neurons after stroke, traumatic brain injury and aid in the partial recovery of multiple sclerosis.