Steve Burden, PhD

Steve-BurdenProfessor and Coordinator of the Molecular Neurobiology Program
Ph.D., 1977 University of Wisconsin

Molecular Neurobiology Program
Skirball Institute of Biomolecular Medicine
540 First Avenue 5th floor
New York, N.Y. 10016
Tel: (212) 263-7341
Fax: (212) 263-8214
E-mail: steve.burden@med.nyu.edu
Lab Website: http://skirball.med.nyu.edu/research/mn/burdenlab/

Research Theme(s): Developmental neurobiology, signal transduction, Stem cell biology
Keywords: Neuromuscular Disease, Stem Cells, Skeletal Muscle

Research Summary:

Signaling mechanisms of neuromuscular synapses formation in mice

Understanding how signals are exchanged at neuromuscular synapses is fundamental to understanding the principles that govern the formation and function of synapses in the peripheral and central nervous systems. The discovery of genes critical for forming and maintaining neuromuscular synapses has not only provided insight into the normal mechanisms for synapse formation but also led to the identification of genes that are responsible for congenital myasthenia and for understanding how mutations in these genes lead to deficits in neuromuscular synapse. Further, because molecules and mechanisms that direct the formation and maintenance of neuromuscular synapses are likely to be utilized in the central nervous system, understanding how neuromuscular synapses form and work remains a paradigm for gaining insight into the types of signaling mechanisms that regulate synapse formation and function in the central nervous system as well. Our lab uses multiple approaches, including molecular genetics, biochemistry and structural biology to understand how neuromuscular synapses form during development and how synapses are maintained and stabilized in adults.

We use mouse molecular genetics and molecular biological approaches to study the mechanisms that regulate the formation of neuromuscular synapses, the single synapse essential for survival. Neuromuscular synapse formation is a multi-step process requiring coordinated interactions between motor neurons and muscle fibers, which lead to the formation of a highly specialized postsynaptic membrane and a highly differentiated nerve terminal. As a consequence, acetylcholine receptors (AChRs) become highly concentrated in the postsynaptic membrane and arranged in perfect register with active zones in the presynaptic nerve terminal, insuring for fast, robust and reliable synaptic transmission. The signals and mechanisms responsible for this process are poorly understood but require Agrin, a neurally derived ligand, Lrp4, the receptor for Agrin, and MuSK, the receptor tyrosine kinase that transduces the Agrin signal. These genes play critical roles in synaptic differentiation, as synapses do not form in their absence. Moreover, mutations in Agrin, MuSK or downstream effectors cause a reduction in the number of AChRs at synapses and are responsible for congenital myasthenia in humans. Further, auto-antibodies to Lrp4, MuSK or AChRs, which cause accelerated degradation of AChRs and structural disorganization of the synapse, are responsible for myasthenia gravis.

Understanding how mutations in the MuSK signaling pathway cause congenital myasthenia and identifying therapies for neuromuscular diseases is hindered by the absence of good cell-based model systems, such as cultured muscle cells from CMS patients. For certain diseases of skeletal muscle, muscle satellite cells, which can be isolated from muscle biopsy tissue, can serve as a source of human skeletal muscle cell lines. Satellite cells, however, are only abundant in muscle undergoing repetitive cycles of degeneration and regeneration (e.g. muscular dystrophy) and are rare in muscle undergoing static wasting (e.g. atrophy) without degeneration/regeneration, as is the case for CMS. For this reason, satellite cells are not a suitable source of cells for studying neuromuscular diseases. Unfortunately, reliable and reproducible methods for converting ES cells or iPS cells to skeletal muscle are not available. Moreover, although forced expression of MyoD or MyoD-family members efficiently converts murine fibroblasts to skeletal muscle, MyoD is ineffective in converting human fibroblasts to muscle. For these reasons, we are examining alternative strategies for converting human skin fibroblasts, isolated from CMS patients, to skeletal muscle in order to establish a cell-based assay system to screen for therapeutics that improve neuromuscular function.

Research supported by NIH

 

Selected Publications