The MBI regulatory sequence of the myelin basic protein (MBP) gene spanning between nucleotides -14 to -50 with respect to the transcription start site is critical for cell type-specific transcription of the MBP gene which encodes the major protein component of the myelin sheath in the central nervous system (CNS). Our recent studies have indicated that the MB1 sequence binds to a developmentally controlled DNA-binding protein from mouse brain named MEF-1/Pur alpha. MEF- 1/Pur alpha increases the promoter activity of MBP in an in vitro transcription system and has the ability to stimulate transcription of the MBP gene in oligodendrocytic cell lines. MEF-1/Pur alpha exhibits binding ability to the JCV early protein, T-antigen. Overexpression of JCV T-antigen in oligodendrocytic cell lines abrogates transcriptional activation of the MBP promoter by MEF-1/Pur alpha. JCV is a human neurotropic virus which upon replication in the CNS induces demyelination due to the lytic destruction of oligodendrocytes. In addition, results from transgenic animals have indicated that, in the absence of the entire viral genome, expression of JCV-T antigen in oligodendrocytes causes dysmyelination of the CNS. Biochemical studies have indicated a substantial decrease in the level of myelin gene expression in these animals. Thus, we hypothesize that the association of JCV T-antigen with MEF-1/Pur alpha functionally inactivates MEF- 1/Pur alpha and results in aberrant expression of MBP and other myelin genes in experimental animals. Results from protein-protein studies have indicated that MEF-1/Pur alpha interacts with the cellular protein p107, which belongs to the retinoblastoma tumor suppressor gene family. Overexpression of p107 in oligodendrocytic cells decreases the level of MBP gene transcription, suggesting that p107 may represent the cellular homologue for JCV T-antigen, which may modulate activity of the MEF- 1/Pur alpha transcription factor during brain development. To evaluate our hypothesis, we plan to: I) determine the level of MEF-1/Pur alpha gene expression and its association with the MB1 motif of MBP in transgenic mice during brain development; ii) examine the association of MEF-1/Pur alpha and JCV T-antigen in transgenic mice and control littermates at various stages of brain development; iii) identify protein regions which are required by T-antigen to associate with and inactivate the transcriptional function of MEF-1/Pur alpha; iv) determine the requirements for continual expression of T-antigen to inactivate of MEF- 1/Pur alpha and induce hypomyelination of CNS; and v) investigate the potential of p107 in modulating MBP gene transcription through MEF- 1/Pur alpha pathway and identify and characterize other potential cellular proteins, which upon interaction with MEF-1/Pur alpha, modify its activity during brain development. The use of JCV T-antigen in a transgenic mouse model provides an excellent opportunity to decipher the regulatory mechanisms involved in the control of myelin gene expression in normal and disease states.
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