Glial cell line-derived neurotrophic factor and developing mammalian motoneurons: Regulation of programmed cell death among motoneuron subtypes

Because of discrepancies in previous reports regarding the role of glial ce ll line-derived neurotrophic factor (GDNF) in motoneuron (MN) development a nd survival, we have reexamined MNs in GDNF-deficient mice and in mice expo sed to increased GDNF after in utero treatment or in transgenic animals ove rexpressing GDNF under the control of the muscle-specific promoter myogenin (myo-GDNF). With the exception of oculomotor and abducens MNs, the surviva l of all other populations of spinal and cranial MNs were reduced in GDNF-d eficient embryos and increased in myo-GDNF and in utero treated animals. By contrast, the survival of spinal sensory neurons in the dorsal root gangli on and spinal interneurons were not affected by any of the perturbations of GDNF availability. In wild-type control embryos, all brachial and lumbar MNs appear to express the GDNF receptors c-ret and GFR alpha 1 and the MN markers ChAT, islet-1, and islet-2, whereas only a small subset express GFR alpha 2. GDNF-depende nt MNs that are lost in GDNF-deficient animals express ret/GFR alpha 1/isle t-1, whereas many surviving GDNF-independent MNs express ret/GFR alpha 1/GF R alpha 2 and islet-1/islet-2. This indicates that many GDNF-independent MN s are characterized by the presence of GFR alpha 2/islet-2. It seems likely that the GDNF-independent population represent MNs that require other GDNF family members (neurturin, persephin, artemin) for their survival. GDNF-de pendent and -independent MNs may reflect subtypes with distinct synaptic ta rgets and afferent inputs.