Glial Cell Line-Derived Neurotrophic Factor and Target-Dependent Regulation of Large-Conductance K_CaChannels in Developing Chick Lumbar Motoneurons

Abstract

The functional expression of large-conductance Ca 2ϩ -activated K ϩ (K Ca ) channels in lumbar motoneurons (LMNs) of the developing chick embryo is regulated in part by interactions with striated muscle target tissues. Here we show that the functional expression of K Ca channels in LMNs developing in vitro can be stimulated by application of a skeletal muscle extract (MEX) or by coculture with hindlimb myotubes. A similar stimulation of K Ca channels in vitro can be produced by the trophic factors glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor but not by neurotrophin (NT)-3 or NT-4. The actions of MEX and hindlimb myotubes are blocked by a GDNF-neutralizing antiserum. Moreover, injection of this same antiserum into the embryonic hindlimb reduced the functional expression of K Ca channels in vivo to levels seen in LMNs deprived of interactions with the hindlimb. The effects of GDNF on K Ca channel expression in LMNs require 24 hr of continuous exposure to reach maximum and are blocked by the translation inhibitor anisomycin, indicating the need for synthesis of new proteins. GDNF actions are also blocked by the farnesyl transferase inhibitor manumycin, suggesting a role for Ras in the actions of GDNF. Finally, the actions of GDNF are inhibited by PP2, an inhibitor of Src family tyrosine kinases, and by LY29003, an inhibitor of phosphatidylinositol 3 kinases, but not by PD98059, an inhibitor of the Erk signaling cascade. None of these treatments alter expression of voltage-activated Ca 2ϩ channels. Thus, the actions of GDNF on LMN K Ca channel expression appear to use a transduction pathway similar to that used for regulation of apoptosis.

A search for genes that may confer divergent morphology and function in the carotid body between two strains of mice

“…Decreased expression of Arnt2 may lead to less expression of Gdnf in the A/J CB (Tables 3 and 5), although Sim1 expression is not significantly different between both strains. Gdnf has been shown to regulate BK channel expression in chick lumbar spinal motoneurons (69). We found that gene expression for BK channel ␤ 2 -subunit (Kcnmb2) is lower in the CB of A/J mice, suggesting a regulatory role of Gdnf in BK channel expression in the CB as well.…”

Temporally tuned neuronal differentiation supports the functional remodeling of a neuronal network in Drosophila

“…In many neurons, the expression of genes critical for mature function (such as neuropeptides, neurotransmitter biosynthetic enzymes, or ion channels) or mature axon or dendritic branching patterns are induced only after many other aspects of neuronal identity are established. In many cases, these late-expressed genes also depend upon extrinsic input for their expression (26,41,42). Thus, here we refer to "terminal differentiation" as the completion of a protracted differentiation process required for mature function.…”

BDNF rescues myosin heavy chain IIB muscle fibers after neonatal nerve injury

“…Excitability modifications of motor neurons, which may be modulated in part by BDNF, are determined by the composition of synaptic inputs and ionic channels on motor neurons during neonatal development (35,36). In fact, BDNF upregulates the potassium conductance that is required for high-frequency firing of motor neurons inner- vating MyHC IIB fibers (27). Therefore, it is conceivable that during early postnatal development, muscle-derived BDNF alters the electrical properties of motor neurons innervating MyHC IIB fibers toward those with lower excitability and a high-frequency phasic pattern of activation.…”