Brian A. Pierchala

Neurotrophic Factors in Neural Development and Disease

Assistant Professor

PhD (1994-1998) Johns-Hopkins School of Medicine
Post-doctoral fellow, Neuroscience (1998-2002) Washington University School of Medicine
Research Instructor (2002-2005) Washington University School of Medicine
Assistant Professor (2005) University at Buffalo

Address Information

Brian A. Pierchala
Department of Biological Sciences
341 Cooke Hall
State University of New York at Buffalo
Buffalo, NY 14260
Phone: (716) 645-2363 Ext. 144
e-mail: bap7@buffalo.edu

Employment Opportunities

My laboratory investigates how neurotrophic factors guide the development and maintenance of the nervous system. We focus predominantly on a family of neurotrophic factors known as the glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs). The GFLs are comprised of four homologous molecules (GDNF, neurturin, artemin, and persephin) that are critical for neural development, kidney morphogenesis, and spermatogenesis.  GFLs, such as neurturin, are also required for the maintenance of the metabolic and phenotypic status, i.e. “trophic” status, of adult neurons.  The neurotrophic activities of GFLs are conveyed via activation of their receptor tyrosine kinase, c-Ret. GFLs do not bind directly to Ret to activate it, but instead bind with high affinity to GPI-anchored coreceptors termed GFRas that, as a GFL-GFRa complex, activate Re

SELECTED RESEARCH PROJECTS

• Determination of the function of lipid rafts in vivo

GDNF deletion is lethal perinatally. Ret deletion phenocopies the knockout of GDNF in mice in regards to development of the kidneys and enteric nervous system. Although GDNF is expressed in the nervous system and periphery in adulthood, the functions of GDNF are largely unresolved due to the early death of the GDNF and Ret knockout mice. To avoid this limitation, we have generated function-blocking GDNF antibodies that were cleaved to produce Fab fragments. Injection of these anti-GDNF Fab fragments into rodents inhibits GDNF without eliciting a non-specific immune response. This approach is allowing us to examine the function of GDNF and Ret in the postnatal development and maintenance of the neuromuscular junction, craniofacial sensory and motor neurons, and taste buds.

 

• Determination of whether GFLs function as long-distance growth factors

Neurotrophic factors are often produced by the targets of neuronal innervation and activate receptors on the nerve terminals. The distance between the axon terminal and the cell body, where the neurotrophic signal must ultimately travel in order to promote the survival and growth of the neuron, is often a huge distance. The distance between the motor endplate and the cell body of a motor neuron that resides in the spinal cord, for example, can be a meter long. How neurotrophic factors promote signals retrogradely over long distances is an area of intense interest in neurobiology. Whether GFLs act over long distances as target-derived neurotrophic factors is unresolved. Using compartmentalized cultures of sympathetic and sensory neurons, a unique culture system that separates biochemically the cell bodies from the distal axons, my laboratory is examining whether GFLs can signal from axon terminals, and by what mechanism this is accomplished.

• Determination of the postnatal functions of GDNF and Ret

GDNF deletion is lethal perinatally. Ret deletion phenocopies the knockout of GDNF in mice in regards to development of the kidneys and enteric nervous system. Although GDNF is expressed in the nervous system and periphery in adulthood, the functions of GDNF are largely unresolved due to the early death of the GDNF and Ret knockout mice. To avoid this limitation, we have generated function-blocking GDNF antibodies that were cleaved to produce Fab fragments. Injection of these anti-GDNF Fab fragments into rodents inhibits GDNF without eliciting a non-specific immune response. This approach is allowing us to examine the function of GDNF and Ret in the postnatal development and maintenance of the neuromuscular junction, craniofacial sensory and motor neurons, and taste buds.

Research Support

NIH, K01 NS045221-05, PI
Title: Ligand-dependent and ligand-independent Ret signal transduction

NYS Spinal Cord Injury Research Program/ SCIRB07-18, PI
Title:  Investigation of GDNF in Neuronal Survival and Maintenance

NIH, R01, NS058510, PI
Title: Survival and growth-promotion mechanisms of the GDNF family ligands (GFLs)

SELECTED PUBLICATIONS