The precise balance for the survival/apoptosis process is fundamental for embryonic development and maintenance of adult organs. Growth factors that influence the survival of the neurons help to guard against natural occurring attrition of the nervous system from aging and are potential therapeutic agents for effective treatment of neurodegenerative diseases. My laboratory is interested in the cellular and molecular mechanism mediating cell survival and/or apoptosis determined by glial cell line-derived neurotrophic factor (GDNF), originally discovered as a potent survival factor for midbrain dopaminergic (DA) neurons. Employing targeted mutagenesis approaches, we have uncovered widespread defects in the developing and adult peripheral and central nervous systems in GDNF deficient mice. GDNF -/- mice die at birth due to absence of both kidneys. However, initial studies of GDNF knockout mice reveal no obvious defects in the midbrain DA neurons at birth. In collaboration with Dr. Granholm, we recently demonstrated in vivo evidence for the involvement of GDNF in postnatal development of the ventral midbrain DA neurons, using a grafting techniques. In the absence of GDNF during development, there is a marked reduction in DA neuronal number and fiber outgrowth in grafts from GDNF-/- midbrain, suggesting an intrinsic failure of GDNF-/- midbrain DA neurons to survive and differentiate in the wildtype environment (J. Neuroscience). These results inspired additional studies using a conditional expression approach to define the role of GDNF in DA neuron development and differentiation in situ and to explore the potential link between GDNF deficiency and Parkinsons disease susceptibility. In addition to the midbrain DA neurons, a special group of DA neurons located in the ventral tegmental area in the brain is also dependent on GDNF for proper function. Mice missing one copy of the functioning GDNF are more susceptible than wildtype controls in response to drugs of abuse (Neuron). This work provided the first genetic evidence for the involvement of GDNF in the adaptation to drugs of abuse. Further studies on the downstream mechanism of GDNF signaling during drug adaptation will be of tremendous potential for developing anti-drug therapeutics. Among the neuronal populations that GDNF supports for their survival are spinal motoneurons, midbrain DA neurons and DA neurons in the ventral tegmental area. Previous studies demonstrated a substantial motoneuron loss in GDNF homozygous mutant spinal cord. Motoneuron loss is the hallmark of the devastating disease of Amyotrophic Lateral Sclerosis (ALS). However, the role of GDNF during motoneuron development and survival has been ill-defined and controversial. In collaboration with Dr. Oppenheim, we have re-examined motoneurons in GDNF deficient mice and in mice exposed to increased GDNF following in utero treatment or in transgenic animals over-expressing GDNF under the control of the muscle specific promoter myogenin (myo-GDNF). With the exception of oculomotor and abducens motoneurons, the survival of all other populations of spinal and cranial motoneurons was reduced in GDNF deficient embryos and increased in myo-GDNF and in utero treated animals. By contrast, the survival of spinal sensory neurons in the dorsal root ganglion and spinal interneurons was not affected by any of the perturbations of GDNF availability. Thus, GDNF is the first growth factor qualified as a bona fide motoneuron survival factor in vivo. We further define motoneuron sub-populations that are GDNF dependent, using a quantitative approach. In wild-type control embryos, all brachial and lumbar motoneurons appear to express the GDNF receptors c-ret, and GFRa1 and the motoneuron markers choline acetyl transferase (ChAT), islet-1 and islet-2, whereas only a small sub-set express GFRa2. We found that motoneurons are lost in GDNF deficient animals, i.e. GDNF dependent express ret/GFRa1/islet-1, whereas many surviving GDNF independent motoneurons express ret/GFRa1/GFRa2 and islet-1/islet-2. This indicates that many GDNF independent motoneurons are characterized by the presence of GFRa2/islet-2. It seems likely that the GDNF independent population represent motoneurons that require other GDNF family members (Neuruturin, Persephin, Artemin) for their survival. Our data suggested that GDNF dependent and independent motoneurons may reflect sub-types with distinct synaptic targets and afferent inputs (J. Neuroscience).
| 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 |
