GDNF Acts through PEA3 to Regulate Cell Body Positioning and Muscle Innervation of Specific Motor Neuron Pools

Abstract

Target innervation by specific neuronal populations involves still incompletely understood interactions between central and peripheral factors. We show that glial cell line-derived neurotrophic factor (GDNF), initially characterized for its role as a survival factor, is present early in the plexus of the developing forelimb and later in two muscles: the cutaneus maximus and latissimus dorsi. In the absence of GDNF signaling, motor neurons that normally innervate these muscles are mispositioned within the spinal cord and muscle invasion by their axons is dramatically reduced. The ETS transcription factor PEA3 is normally expressed by these motor neurons and fails to be induced in most of them in GDNF signaling mutants. Thus, GDNF acts as a peripheral signal to induce PEA3 expression in specific motor neuron pools thereby regulating both cell body position and muscle innervation.

Gamma and alpha motor neurons distinguished by expression of transcription factor Err3

“…It remains to be determined whether GDNF signaling has an early role in the specification of gamma motor neuron identity, in addition to its later gamma survival-promoting activity. Nevertheless, the idea that peripherally derived GDNF directs the transcriptional specification of motor neuron subtype identity at embryonic stages has a precedent in the induction of ETS gene expression by motor pools (8,27,38). Thus trophic factors such as GDNF may have sequential functions in the assignment of pool and intrapool transcriptional identities.…”

Onset of ETS expression is not accelerated by premature exposure to signals from limb mesenchyme

“…Thus, axons from diverse populations of motor neurons should be exposed to ETS initiating signals following perturbation of the spatiotemporal pattern of retinoid signaling. Despite this, in segments LS1-LS3 both Er81 and Pea3 were expressed in only the appropriate populations of motor neurons (data not shown), confirming that only neurons in specific motor pools are competent to respond to ETS-inducing signals (Lin et al, 1998;Haase et al, 2002;Wang and Scott, 2004). Furthermore, Er81 expression rarely extended more caudally in lLMC neurons in the presence of exogenous retinoic acid, although motor neurons in segment LS4, which normally do not express Er81, are competent to do so if exposed to the appropriate peripheral signals (Wang and Scott, 2004, see also above).…”

“…PEA3 function in motor neurons is better understood. PEA3 is required for the expression of Cadherin-8 and Semaphorin-3E in motor neurons (Livet et al, 2002), for the settling of motor neurons in the correct position in the LMC (Ladle and Frank, 2002;Livet et al, 2002;Vrieseling and Arber, 2006), the orientation of motor neuron dendrites and the specificity of sensory-motor connectivity (Vrieseling and Arber, 2006; but see Ladle and Frank, 2002), and the growth and branching of motor axons within the target muscles (Haase et al, 2002;Ladle and Frank, 2002;Livet et al, 2002). A role for PEA3 in sensory neurons has not been established (Ladle and Frank, 2002).…”

“…Expression of both Pea3 and Er81 requires limbderived signals (Lin et al, 1998;Price et al, 2002;Wang and Scott, 2004). Glial cell-line derived neurotrophic factor (GDNF) produced by mesenchymal cells in the limb (Haase et al, 2002), in conjunction with factors acting through the HGF receptor Met (Helmbacher et al, 2003), has been shown to initiate Pea3 expression in brachial motor neurons. Other earlier factors must establish the competence to express PEA3, because only the appropriate motor neurons express PEA3 upon exposure to GDNF in vitro (Haase et al, 2002).…”

“…Glial cell-line derived neurotrophic factor (GDNF) produced by mesenchymal cells in the limb (Haase et al, 2002), in conjunction with factors acting through the HGF receptor Met (Helmbacher et al, 2003), has been shown to initiate Pea3 expression in brachial motor neurons. Other earlier factors must establish the competence to express PEA3, because only the appropriate motor neurons express PEA3 upon exposure to GDNF in vitro (Haase et al, 2002). Neurotrophin-3 (NT3) triggers expression of ER81 in sensory neurons, but not in motor neurons (Patel et al, 2003;Li et al, 2006).…”