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The GDNF family: Signalling, biological functions and therapeutic value

Key Points

  • Four different glial cell line-derived neurotrophic factor (GDNF)-family ligand (GFL)– receptor (GFRα) binding pairs exist, and they all signal through the transmembrane RET receptor tyrosine kinase.

  • Recruitment of RET to lipid rafts, induced by GFL binding to glycolipid-anchored GFRα receptors, is necessary for efficient downstream signalling. RET stimulation by soluble or matrix-bound GFL–GFRα complex activates distinct signalling pathways outside the rafts, and leads to sustained signalling inside the rafts.

  • Regulation of GFL and soluble GFRα receptor production, their interactions with the extracellular matrix, as well as internalization and degradation of the GFL–GFRα–RET receptor complex, are poorly understood.

  • GDNF acts in synergy with other growth factors, including transforming growth factor-β, but the mechanisms are unclear. Nerve growth factor (NGF) can activate RET by its tyrosine kinase receptor TrkA through an unknown intracellular pathway, independently of GFLs and GFRα receptors. GDNF can activate Src-family kinases through GFRα1 and an unknown transmembrane linker protein in a RET-independent manner.

  • GFLs might regulate the expression of their cognate co-receptors. Regulation of neurotransmitter release by GDNF implies a role in synaptic plasticity.

  • Sympathetic precursors require artemin, which is produced locally or by intermediate target cells, primarily for migration, but also for proliferation and early differentiation. Similarly, parasympathetic and enteric precursors require GDNF.

  • During target innervation, sympathetic neurons become dependent on NGF rather than artemin for their survival. By contrast, parasympathetic neurons switch their requirements from GDNF to target-derived neurturin for terminal innervation and the maintenance of cell size.

  • In somatic sensory neurons, GFLs regulate soma size, target innervation and nociception, but are not required for survival in vivo.

  • A subpopulation of motor neurons requires GDNF, which is produced by Schwann cells, to avoid programmed cell death. GDNF- but not brain-derived neurotrophic factor-mediated protection of injured motor neurons requires inhibitor of apoptosis proteins. So, trophic signalling differs between neurotrophins and GFLs.

  • Apart from promoting neuronal maintenance and regeneration, GFL-like drugs might be useful in the treatment of disorders such as neuropathic pain and addiction.

Abstract

Members of the nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF) families — comprising neurotrophins and GDNF-family ligands (GFLs), respectively — are crucial for the development and maintenance of distinct sets of central and peripheral neurons. Knockout studies in the mouse have revealed that members of these two families might collaborate or act sequentially in a given neuron. Although neurotrophins and GFLs activate common intracellular signalling pathways through their receptor tyrosine kinases, several clear differences exist between these families of trophic factors.

Figure 1: GDNF-family ligands and receptor interactions.
Figure 2: Distinct GDNF-family ligand signalling inside and outside rafts.
Figure 3: Model of RET-independent GDNF–GFRα1 signalling.
Figure 4: Differences in trophic factor dependence between sympathetic and parasympathetic neurons.
Figure 5: In vivo functions of GDNF-family ligands in somatic sensory and motor neurons.

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Acknowledgements

We thank U. Arumäe, M. Paveliev, J. Rossi and P. Runeberg-Roos for critical reading of the manuscript. Our work is supported by the Academy of Finland, TEKES, Biocentrum Helsinki and the Sigrid Jusélius Foundation. Owing to space limitations, we have cited original references only from the last four years; we apologize for the omission of earlier papers.

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DATABASES

LocusLink

ARTN

BDNF

CREB

DOK4/5

Edn3

Ednrb

enigma

frequenin

FRS2

GDNF

GFRα

GRB2

IRS1/2

NAIP

NGF

NRTN

NT-3

P75NTR

Pax3

Phox2b

PSPN

Rac

RET

Shc

SIP1

SOX10

Src

TGF-β

TrkA

XIAP

OMIM

congenital central hypoventilation syndrome

Hirschsprung's disease

Parkinson's disease

FURTHER INFORMATION

The Genome Database 

Encyclopedia of Life Sciences

motor neuron diseases

Parkinson disease

trophic support

Glossary

CYSTINE KNOT

A structural motif that consists of six cysteine residues that are linked together by three disulphide bonds. It is involved in protein stabilization and dimer formation.

HEPARAN SULPHATE

A glycosaminoglycan that consists of repeated units of hexuronic acid and glucosamine residues. It usually attaches to proteins through a xylose residue to form proteoglycans.

RECEPTOR TYROSINE KINASE

Any of a family of transmembrane receptors, the intracellular domains of which catalyse the phosphorylation, by ATP, of specific tyrosine residues on their target proteins.

GLYCOSYL PHOSPHATIDYLINOSITOL

A post-translational modification, the function of which is to attach proteins to the exoplasmic leaflet of membranes, possibly to specific domains therein. The anchor is made of one molecule of phosphatidylinositol to which a carbohydrate chain is linked through the C-6 hydroxyl of the inositol, and is attached to the protein through an ethanolamine phosphate moiety.

PETROSAL GANGLION

A structure that contains the cell bodies of the sensory neurons of the glossopharyngeal nerve, which innervate the tongue, pharynx, middle ear and carotid body.

LAMELLIPODIA

Sheet-like extensions at the edge of cells that contain a crosslinked F-actin meshwork.

C-FOS

An immediate early gene that is rapidly turned on when many types of neuron increase their activity. It can therefore be used to identify responsive neurons.

ENDOTHELIN

A molecule with potent vasoconstrictor activity. It is expressed by vascular cells, as well as in brain, kidney and lung.

CAROTID BODY

A chemoreceptor organ that is located above the bifurcation of the common carotid artery. It monitors changes in blood O2 and CO2 content, and pH, thus helping to control respiratory activity.

SKIN–NERVE PREPARATION

An in vitro preparation that is used to study the functional properties of sensory neurons that innervate the skin. Single sensory afferents are isolated by recording from axons in microdissected filaments of a cutaneous nerve, and are classified on the basis of their conduction velocity, mechanical threshold and adaptation properties.

INTRATHECAL

Administered into the outer sheath of the spinal cord.

KINDLING

An experimental model of epilepsy in which an increased susceptibility to seizures arises after daily focal stimulation of specific brain areas (for example, the amygdala) — stimulation that does not reach the threshold to elicit a seizure by itself.

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Airaksinen, M., Saarma, M. The GDNF family: Signalling, biological functions and therapeutic value. Nat Rev Neurosci 3, 383–394 (2002). https://doi.org/10.1038/nrn812

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