Developmental regulation of GDNF response and receptor expression in the enteric nervous system

Abstract

The development of the enteric nervous system is dependent upon the actions of glial cell line-derived neurotrophic factor (GDNF) on neural crest-derived precursor cells in the embryonic gut. GDNF treatment of cultured enteric precursor cells leads to an increase in the number of neurons that develop and/or survive. Here we demonstrate that, although GDNF promoted an increase in neuron number at all embryonic ages examined, there was a developmental shift from a mitogenic to a trophic response by the developing enteric neurons. The timing of this shift corresponded to developmental changes in gut expression of GFR alpha-1, a co-receptor in the GDNF-Ret signaling complex. GFR alpha-1 was broadly expressed in the gut at early developmental stages, at which times soluble GFR alpha-1 was released into the medium by cultured gut cells. At later times, GFR alpha-1 became restricted to neural crest-derived cells. GFR alpha-1 could participate in GDNF signaling when expressed in cis on the surface of enteric precursor cells, or as a soluble protein. The GDNF-mediated response was greater when cell surface, compared with soluble, GFR alpha-1 was present, with the maximal response seen the presence of both cis and trans forms of GFR alpha-1. In addition to contributing to GDNF signaling, cell-surface GFR alpha-1 modulated the specificity of interactions between GDNF and soluble GFR alphas. These experiments demonstrate that complex, developmentally regulated, signaling interactions contribute to the GDNF-dependent development of enteric neurons.

Mitogenic effect of glial cell line-derived neurotrophic factor is dependent on the activation of p70S6 kinase, but independent of the activation of ERK and up-regulation of Ret in SH-SY5Y cells

“…The mitogenic action of GDNF has been mainly described in mammalian enteric nervous system progenitors. GDNF increases the uptake of BrdU from neuronal crest cells immunoisolated from the gut of quail or rat embryo [18,45]. While GDNF and neurturin, another member of the GDNF family, greatly increase the number of BrdU/Ret double-labeled enteric neuron precursors, removal of GDNF or neurturin from the culture medium decreases cell proliferation [20].…”

Reawakening GDNF's regenerative past in mice and humans

“…2 C). This phenomenon may be similar to gut development, where GFRα1-positive enteric neuron precursors migrate down the gut mesenchyme, which produces GDNF [ 72 , 73 ]. Nonetheless, a few cells in the upper dermal papillary compartment express Gdnf , which may be sufficient to stimulate neogenic hair formation after wounding.…”

GDNF neurotrophic factor signalling determines the fate of dermal fibroblasts in wound‐induced hair neogenesis and skin regeneration

“…Gdnf was found to be expressed primarily by lower‐repair‐competent dermal fibroblasts, implying the formation of a ‘new’ GDNF‐rich substratum to support the wound environment, similar to how it is seen in early organ development. 39 , 40 Furthermore, Gdnf and Gfra1 are expressed by neuronal‐like cells and dermal fibroblasts in neonatal regeneration‐competent skin wounds. 41 Although older 21‐day‐old animals had Gfra1 expression in neuronal‐like cells, there was less transcript in dermal fibroblasts than in neonatal wounds.…”