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Increasing the Specificity of Neurotrophic Factors

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Increasing the Specificity of Neurotrophic Factors COMMENTARY Increasing the specificity of neurotrophic factors Moses V. Chao1 The Skirball Institute of Biomolecular Medicine, New York University, New York, NY 10016 eurotrophic factors are capable of accomplishing many tasks. In N addition to regulating neural cell survival and differentiation, they can influence changes in synaptic transmission and higher order behaviors, such as aggression, addiction, depression, learning, and memory. Because many tro- phic factors use receptor tyrosine kinases as a means for initiating signaling, a major question is how tyrosine phosphorylation events that lead to canonical MAP kinase, Akt, and phospholipase C-γ activities can account for so many diverse outcomes (1). The article in PNAS by Schalm et al. (2) on protocadherins and the glial-derived neu- rotrophic factor (GDNF) provides a unique insight into this question. GDNF is an important protein that was discovered in 1993 as a potent survival factor for midbrain dopaminergic neurons (3). It has been frequently touted as a treatment for Parkinson’s disease. GDNF Fig. 1. A link between GDNF and protocadherins. A multitude of different protocadherin proteins are also exerts trophic effects on sympathetic, expressed in the nervous system. Each transmembrane protocadherin possesses six extracellular cad- sensory, parasympathetic, and enteric neu- herin domains and a short cytoplasmic segment. In the mouse, there are 14 protocadherin-α genes, 22 rons. The effects of GDNF and the related protocadherin-β genes, and 22 protocadherin-γ genes, which undergo multiple splicing events (16, family members neurturin, artemin, and 17). The GDNF family of ligands (GDNF, neurturin, artemin, and persephin) bind to individual GDNF-α persephin are mediated by RET, a trans- receptors (GFR-α), which form a complex with the RET tyrosine kinase (5). The specific protocadherin membrane receptor tyrosine kinase. GDNF proteins α4andγb7 are phosphorylated by RET after GDNF treatment, which, in turn, stabilizes RET ligands do not bind directly to RET but and delays its degradation (2). require GPI-anchored coreceptors [called GDNF receptor-α1–4] to activate the RET teracting protein of protocadherin-α4. In- junctions (8) has been backed by the ap- receptor, which efficiently increases in- terestingly, the interaction of RET with pearance of fewer and weaker synapses tracellular ERK and PI3K activities and 2+ protocadherin-α4 is specific and involves in spinal cord neurons in mice carrying Ca levels (4, 5). Many biological func- the extracellular domains of each protein, γ tions are affected by these ligand-receptor a large deletion in the protocadherin- events, including proliferation and migra- which both share similar cadherin-like gene cluster (11). motifs (Fig. 1). Moreover, the absence of multiple tion of progenitor cells, axon guidance, and γ chemoattraction (5). GDNF is also involved How are protocadherins relevant to -protocadherins results in dramatic neu- RET? Protocadherin-α was originally rodegeneration of spinal cord motor neu- in synapse formation and neuronal excit- fi fi ability in possessing the ability to modulate identi ed as a brain-speci c protein that rons (12), reminiscent of what happens postsynaptic currents in dopaminergic neu- interacted with the Fyn nonreceptor tyro- when there is a lack of trophic support. rons (6). Recently, considerable interest has sine kinase (8). It quickly became apparent Hence, protocadherins display multiple centered on the roles of GDNF to regulate that the protocadherin gene family rep- roles in the nervous system. In this re- drugs of abuse, such as cocaine and mor- resented the largest subgroup of the cad- gard, RET signaling is responsible for the phine, negatively as well as alcohol addic- herin superfamily, consisting of three survival and function of many neuron α β γ tion (7). The breadth of actions of GDNF tandemly arrayed gene clusters: , , and populations. The phosphorylation of family members begs for more mechanistic (9, 10). As a transmembrane protein with protocadherins by GDNF is therefore an insights to account for the specificity and a short cytoplasmic domain, each proto- important observation that implies an extent of RET receptor signaling and its cadherin is distinguished by six ectodo- overlap in their respective functions. ability to change synaptic plasticity. main cadherin-like repeats of 100 amino How do protocadherins and RET affect A unique set of mechanisms has now acids. Because there are nearly 70 proto- each other? One clue comes from the been provided by the finding that trans- cadherin genes that undergo a multitude finding that RET receptor levels are ex- membrane protocadherin molecules are of splicing events, a huge number of dif- quisitely sensitive to proteasomal degrada- associated with the RET receptor. Schalm ferent protocadherin proteins can be gen- tion (13, 14). Like many growth factors, et al. (2) report that GDNF causes the erated. For this reason, there has been phosphorylation of specific protocadherin enormous interest by neuroscientists in the proteins in sympathetic and motor neu- past decade in the potential roles of pro- Author contributions: M.V.C. wrote the paper. rons, two responsive populations. These tocadherins as synaptic recognition pro- The author declares no conflict of interest. interactions were uncovered by this group teins. The significance of the localization See companion article on page 13894. with the identification of RET as an in- of protocadherin proteins at synaptic 1E-mail: [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1008518107 PNAS Early Edition | 1of2 Downloaded by guest on September 23, 2021 GDNF binding results in rapid ubiquitina- loss of GDNF-RET signaling or a deficit such as discoidin domain receptor 2 and Src tion of its receptor on lysine residues. There in retrograde transport can lead to neu- family members (2). are additional layers of regulation, be- rodegeneration (14). The responsiveness Protocadherins are found in combina- cause two isoforms of RET that contain of RET receptors is therefore dependent torial expression patterns frequently asso- different lengths of cytoplasmic tails, Ret51 on receptor trafficking and turnover. ciated with synapses, and they have been and Ret9, differ in their response to Phosphorylation of protocadherins after strongly implicated as cell recognition and GDNF. Also, there is cell type specificity. GDNF treatment ensures that RET is not adhesion molecules. It is likely that their In sympathetic neurons, Ret51 is degraded immediately inactivated through degrada- effects will have an impact on the kinetics faster in sympathetic neurons than in sen- tion. The current results suggest that the and strength of signaling of other synaptic sory neurons. However, when the levels of GDNF-RET receptor exists in a large molecules. In addition to mediating neu- protocadherin-α4 are increased in sympa- complex with protocadherin proteins, ronal survival and synaptic development, thetic neurons, the levels of phosphorylated which contribute to RET receptor stability protocadherin-α members have been im- Ret51 are increased. Conversely, lowering and signaling. The existence of an array of plicated in memory and learning (15). the levels of protocadherins brings about different protocadherins and different RET Hence, the association of GDNF with a decrease in the levels of responsive RET isoforms likely generates a diversity of re- the protocadherin family of proteins may receptors (2). Hence, one way in which ceptor complexes with different compo- indeed foreshadow further insights into protocadherins exert an effect on RET is nents, thus simultaneously increasing the molecular basis of neurodegenerative to stabilize the activated receptor and the diversity and specificity of trophic factor diseases and psychiatric disorders. prevent degradation. signaling. Indeed, Schalm et al. (2) report The association of protocadherins with there are other signaling proteins that ACKNOWLEDGMENTS. The figure was composed RET has a number of implications. A de- are associated with protocadherins, includ- by Kenneth Teng, and work on neurotrophic factors in the laboratory of M.V.C. has been lay in degradation of the RET receptor ing leukocyte antigen-related receptor ty- previously supported by National Institutes of allows neurons to survive for a longer pe- rosine phosphatase and protein tyrosine Health Grants NS21072, HD23315, AG25970, riod of time in the presence of GDNF. A phosphatase-α as well as tyrosine kinases, MH086651, and MH090638. 1. Chao MV (1992) Growth factor signaling: Where is the 6. Bourque MJ, Trudeau LE (2000) GDNF enhances the 13. Pierchala BA, Milbrandt J, Johnson EM Jr. (2006) Glial specificity? Cell 68:995–997. synaptic efficacy of dopaminergic neurons in culture. cell line-derived neurotrophic factor-dependent re- 2. Schalm SS, Ballif BA, Buchanan SM, Phillips GR, Eur J Neurosci 12:3172–3180. cruitment of Ret into lipid rafts enhances signaling — Maniatis T (2010) Phosphorylation of protocadherin 7. Carnicella S, Ron D (2009) GDNF A potential target to by partitioning Ret from proteasome-dependent deg- treat addiction. Pharmacol Ther 122:9–18. proteins by the receptor tyrosine kinase Ret. Proc Natl radation. J Neurosci 26:2777–2787. 8. Kohmura N, et al. (1998) Diversity revealed by a novel Acad Sci USA 107:13894–13899. 14. Tsui CC, Pierchala BA (2010) The differential axonal family of cadherins expressed in neurons at a synaptic 3. Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F (1993) degradation
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