fnaya@bu.edu

Developmental Biology Cell Signaling and Gene Regulation Genetics

Frank Naya

Assistant Professor of Biology
Ph.D., Baylor College of Medicine, 1997

Cardiac development and disease, mouse developmental biology, gene regulation

My research is focused on understanding the mechanisms that control tissue-specific gene expression and cell differentiation in cardiac and skeletal muscle. Particular emphasis is placed on dissecting the transcriptional pathways involved in cardiogenesis. There is growing evidence that mutations in cardiac developmental control genes, many of which are transcription factors, often result in cardiac malformations or abnormalities. These studies will help delineate the genetic circuitry employed in muscle development and disease.

Members of the myocyte enhancer factor-2 (MEF2) family of transcription factors play an important role in muscle-specific gene expression and development. There are four mef2 genes, mef2a, mef2b, mef2c, mef2d in vertebrates that are expressed in a highly restricted manner in developing muscle but become more widely expressed postnatally. MEF2 proteins share a highly conserved amino terminal MADS (MCM1, Agamous, Deficiens, Serum Response Factor) box domain required for DNA binding and dimerization. MEF2 proteins bind an A/T-rich DNA sequence as homo- or heterodimers to potently activate transcription of muscle-specific target genes. Although in vitro studies have clearly provided important insights into the function of MEF2 in muscle-specific gene expression, the unique role of each of the mef2 genes in mammalian development has not been completely elucidated. Importantly, a loss-of-function mutation in the single mef2 gene in flies results in the failure of muscle precursor cells to properly differentiate and express muscle structural genes, demonstrating a pivotal function for mef2 in the control of myogenesis.

Given the central role of mef2 in muscle development in flies it will be crucial to inactivate the function of the vertebrate genes in the mouse to gain a complete understanding of this gene family in mammalian myogenesis and development. The only vertebrate mef2 gene to be analyzed by loss-of-function mutations in the mouse is mef2c. Inactivation of the mef2c gene results in defective cardiac morphogenesis and abnormal vascular development. To investigate the functions of mef2a, the predominant mef2 gene expressed in post-natal cardiac and skeletal muscle we generated mef2a null mice by gene targeting. Mice lacking mef2a died suddenly and unexpectedly within a week after birth. Histological and ultrastructural analysis revealed a pronounced dilation of the right ventricle with extensive myofibrillar and mitochondrial disorganization in cardiomyocytes, respectively. To further understand the molecular mechanisms of cardiac sudden death and post-natal cardiomyopathy DNA microarray analysis was initiated to identify downstream genes affected in the mef2a mutant hearts. With the use of DNA microarray analysis we have identified several, novel expressed sequence tags (ESTs) exhibiting changes in gene expression in mef2a mutant hearts. Molecular characterization of these ESTs as well as generating loss-of-function mutations will provide insights into their role in cardiac function and biology. Additional studies will address the unique in vivo role of the remaining mef2 genes in cardiac development and disease using a combination of transgenic and knockout approaches in mice.

Huang, H.-T., O.M. Brand, M. Mathew, C. Ignatiou, E.P. Ewen, S.A. McCalmon, and F.J. Naya. 2006. Myomaxin is a novel transcriptional target of MEF2A that encodes an alpha-actinin-interacting protein. Journal of Biological Chemistry. In press.

Durham, J. T., O. M. Brand, M. Arnold, J. G. Reynolds, L. Muthukumar, H. Weiler, J. A. Richardson, and F. J. Naya. 2006. Myospryn is a direct transcriptional target for MEF2A that encodes a striated muscle, alpha-actinin-interacting, costamere-localized protein. Journal of Biological Chemistry 281:6841-6849.

Talmadge, R. J., J. S. Otis, M. R. Rittler, N. D. Garcia, S. R. Spencer, S. J. Lees, and F. J. Naya. 2004. Calcineurin activation influences muscle phenotype in a muscle-specific fashion. BMC Cell Biology 5:28.

Naya, F.J., B.L. Black, H. Wu, R. Bassel-Duby, J.A. Richardson, J.A. Hill, and E.N. Olson. 2002. Mitochondrial deficiency and cardiac sudden death in mice lacking the MEF2A transcription factor. Nature Med. v.8 (11): 1303-9.

Wu H, Rothermel B, Kanatous S, Rosenberg P, Naya FJ, Shelton JM, Hutcheson KA, DiMaio JM, Olson EN, Bassel-Duby R, Williams RS. 2001. Activation of MEF2 by muscle activity is mediated through a calcineurin-dependent pathway.EMBO J. Nov 15;20(22):6414-23.

Passier, R., H. Zeng, N.Frey, F.J. Naya, R.L. Nicol, T.A. McKinsey, P. Overbeek, J.A. Richardson, S.R. Grant, and E.N. Olson. 2000. CaM Kinase signaling induces cardiac hypertrophy and activates the MEF2 transcription factor in vivo. J. Clin. Investigation. v. 105(10): 1395-406.

Naya, F.J., B. Mercer, J. Shelton, J. Richardson, R.S. Williams, and E.N. Olson. 2000. Stimulation of skeletal muscle fiber type by calcineurin. J. Biol. Chem. v. 275(7): 4545-48.

Naya, F.J. and E.N. Olson. 1999. MEF2: a transcriptional target for signaling pathways controlling skeletal muscle growth and differentiation. Curr. Opin. Cell Biol. v. 11(6): 683-688.

Musaro, A., K.J.A. McCullagh, F.J. Naya, E.N. Olson, and N. Rosenthal. 1999. IGF-I induces skeletal muscle hypertrophy through calcineurin in association with GATA-2 and NF-ATc1. Nature. v. 400(6744): 581-5.

Naya, F.J., C. Wu, J. A. Richardson, P. Overbeek, and E.N. Olson. 1999. Transcriptional activity of MEF2 during mouse embryogenesis monitored with a MEF2-dependent transgene. Development. v. 126(10), 2045-2052.

Questions and comments are always welcome.
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This document was last modified on November 13, 2006.