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

GPI-anchored proteins reside in membrane microdomains known as lipid rafts that function as specialized signaling platforms.  Ret signal transduction in vitro requires its translocation into lipid rafts by GFRas. We have recently discovered that Ret is rapidly ubiquitinated and degraded after activation with GFLs.  Lipid rafts sequester Ret away from the degradation machinery located in non-raft membrane domains, thereby increasing the half-life of activated Ret and sustaining Ret signaling. Although the composition and function of lipid rafts have been analyzed in great detail with regard to signal transduction, controversy continues as to whether lipid rafts are membrane structures that exist under normal physiologic conditions.  We have generated transgenic mice that harbor a mutation that blocks the translocation of the GDNF-activated Ret signaling complex into lipid rafts. The analysis of these mice is allowing us to test the hypothesis that the recruitment of Ret to lipid rafts by is required for GDNF functions such as kidney morphogenesis and enteric nervous system development.

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

Neurotrophic factors are 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.  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.

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