BIOMEDICAL ENGINEERING

Our laboratory seeks to define regulatory interactions in the developing nervous system and to understand how perturbations of development result in disease. In particular, we study the role of neuronal growth factors in the functional maturation of neural systems using genetically engineered mice and tissue culture model systems.

A major focus of the laboratory is to elucidate the molecular pathogenesis of Rett Syndrome (RTT), a devastating developmental disorder characterized by cognitive, motor and autonomic dysfunction, and to develop potential treatments. In particular, we are studying how loss of MeCP2, the gene mutated in RTT, disrupts expression and secretion of Brain Derived Neurotrophic Factor (BDNF), a protein that is critical for development, function and plasticity of many neurons in the brain and peripheral nervous system. We have found that the normal interplay between neuronal activity, and expression and secretion of BDNF, is dysregulated in MeCP2 null mice. In particular, loss of MeCP2 results in a progressive decline in the ability of neurons to synthesize and secrete normal levels of BDNF after birth. Some of the earliest changes occur in brain structures that are critical for the control of breathing and other homeostatic functions that are adversely affected in Rett patients. In fact, MeCP2 null mice exhibit severe respiratory defects, as in RTT patients. Current efforts are focused on defining underlying mechanisms and on developing potential BDNF-based therapies for this disease.

Suggested reading:

Wang, H., Chan, S., Ogier, M., Hellard, D., Wang, Q., Smith, C. and D.M. Katz. (2006) Dysregulation of BDNF expression and neurosecretion in MeCP2 null mice, J. Neuroscience, 26:10911-10915.

Katz, D.M. (2005) Neurotrophic and transcriptional mechanisms of respiratory neuron development, Respiratory Physiology and Neurobiology, 149:99-110 (Review).