The precise balance for the survival and apoptosis is fundamental during development and in adult. Growth factors play critical roles in such balance, and therefore are potential therapeutic agents for effective treatment of a variety of diseases. My laboratory is interested in the cellular and molecular mechanism mediating the diverse functions of glial cell line-derived neurotrophic factor (GDNF). This growth factor was originally discovered as a potent survival factor for midbrain dopaminergic (DA) neurons. It has now been established that GDNF belongs to a family of growth factors that also include neurturin, artemin, and persephin, and their functions are mediated by a family of GPI-linked binding proteins called GFR-a, and a receptor tyrosine kinase called c-RET. Employing targeted mutagenesis approach, we have uncovered widespread defects in developing and adult Gdnf deficient mice. We are continuing our studies on GDNF, using a combination of genetic, biochemical and molecular biological approaches. Gdnf-/- mice die at birth due to defects in the kidney and gastrointestinal track. However, initial studies of Gdnf-/- mice reveal no obvious defects in the midbrain DA neurons at birth. Although GDNF has been shown to prevent lesion-induced death of midbrain DA neurons, its function in normal brain remains unclear. To address this question directly, we study the role of GDNF on DA neurons in cultures and in adult brain slices using an electrophysiological approach. We discovered an unexpected, acute effect of GDNF on A-type potassium channels, leading to a potentiation of neuronal excitability. Further, we show that GDNF regulates the K+ channels through a mechanism that involves activation of MAP kinase. Thus, this study has revealed, for the first time, an acute modulation of ion channels by GDNF. Our findings suggest that the normal function of GDNF is to regulate neuronal excitability, and consequently dopamine release. These results may also have implications in the treatment of Parkinson's disease (Nature Neuroscience). In addition to its role in the central nervous system, GDNF plays a key role during kidney organogenesis. The mesenchymal-derived GDNF induces ureteric bud formation and the subsequent ureteric branching, forming the collecting duct system. Branching morphogenesis is tightly coupled to glomerulogenesis, the formation of the nephron which is the filtering unit of the kidney. Molecular link between branching mrophogenesis and glomerulogenesis is not clear. In collaboration with Dr. Gridley, we discovered that Notch2 signaling may serve as a molecular link. In mice with hypomorphic Notch2 allele, we found abnormal patterning of mesangial cells during glomerulogenesis (Development). This result is particularly interesting in light of our recent finding that a stromal cell derived factor, identified by differential display approach, is reduced in Gdnf-/- mutant mice. Further analysis will be carried out to understand the molecular, cellular and developmental mechanisms in the coupling of branching morphogenesis and nephronogenesis. Understanding this process will yield valuable insights into the mechanism of disease pathogenesis and the basis for genetic predisposition to renal failure in human.
| Granholm, A C; Reyland, M; Albeck, D et al. (2000) Glial cell line-derived neurotrophic factor is essential for postnatal survival of midbrain dopamine neurons. J Neurosci 20:3182-90 |
| Messer, C J; Eisch, A J; Carlezon Jr, W A et al. (2000) Role for GDNF in biochemical and behavioral adaptations to drugs of abuse. Neuron 26:247-57 |
| Oppenheim, R W; Houenou, L J; Parsadanian, A S et al. (2000) Glial cell line-derived neurotrophic factor and developing mammalian motoneurons: regulation of programmed cell death among motoneuron subtypes. J Neurosci 20:5001-11 |
