NTRK3 (TRKC) belongs to the family of neurotrophin receptor tyrosine kinases, which also includes NTRK1 (TRKA) and NTRK2 (TRKB). Neurotrophin-3 (NTF3, also known as NT-3) is the ligand for NTRK3. Similar to other NTRK receptors and receptor tyrosine kinases in general, ligand binding induces receptor dimerization followed by trans-autophosphorylation on conserved tyrosines in the intracellular (cytoplasmic) domain of the receptor (Lamballe et al. 1991, Philo et al. 1994, Tsoulfas et al. 1996, Yuen and Mobley 1999, Werner et al. 2014). These conserved tyrosines serve as docking sites for adaptor proteins that trigger downstream signaling cascades. Signaling through PLCG1 (Marsh and Palfrey 1996, Yuen and Mobley 1999, Huang and Reichardt 2001), PI3K (Yuen and Mobley 1999, Tognon et al. 2001, Huang and Reichardt 2001, Morrison et al. 2002, Lannon et al. 2004, Jin et al. 2008) and RAS (Marsh and Palfrey 1996, Gunn-Moore et al. 1997, Yuen and Mobley 1999, Gromnitza et al. 2018), downstream of activated NTRK3, regulates cell survival, proliferation and motility.
In the absence of its ligand, NTRK3 functions as a dependence receptor and triggers BAX and CASP9-dependent cell death (Tauszig-Delamasure et al. 2007, Ichim et al. 2013).<p>NTRK3 was reported to activate STAT3 through JAK2, but the exact mechanism has not been elucidated (Kim et al. 2016). NTRK3 was reported to interact with the adaptor protein SH2B2, but the biological role of this interaction has not been determined (Qian et al. 1998).<p>Receptor protein tyrosine phosphatases PTPRO and PTPRS (PTPsigma) negatively regulate NTRK3 signaling by dephosphorylating NTRK3 (Beltran et al. 2003, Faux et al. 2007, Hower et al. 2009, Tchetchelnitski et al. 2014). In addition to dephosphorylation of NTRK3 in-cis, the extracellular domain of pre-synaptic PTPRS can bind in-trans to extracellular domain of post-synaptic NTRK3, contributing to synapse formation (Takahashi et al. 2011, Coles et al. 2014).
View original pathway at Reactome.</div>
Tauszig-Delamasure S, Yu LY, Cabrera JR, Bouzas-Rodriguez J, Mermet-Bouvier C, Guix C, Bordeaux MC, Arumäe U, Mehlen P.; ''The TrkC receptor induces apoptosis when the dependence receptor notion meets the neurotrophin paradigm.''; PubMedEurope PMCScholia
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Tsoulfas P, Stephens RM, Kaplan DR, Parada LF.; ''TrkC isoforms with inserts in the kinase domain show impaired signaling responses.''; PubMedEurope PMCScholia
Marsh HN, Palfrey HC.; ''Neurotrophin-3 and brain-derived neurotrophic factor activate multiple signal transduction events but are not survival factors for hippocampal pyramidal neurons.''; PubMedEurope PMCScholia
Fukumoto T, Kubota Y, Kitanaka A, Yamaoka G, Ohara-Waki F, Imataki O, Ohnishi H, Ishida T, Tanaka T.; ''Gab1 transduces PI3K-mediated erythropoietin signals to the Erk pathway and regulates erythropoietin-dependent proliferation and survival of erythroid cells.''; PubMedEurope PMCScholia
Saelens X, Festjens N, Vande Walle L, van Gurp M, van Loo G, Vandenabeele P.; ''Toxic proteins released from mitochondria in cell death.''; PubMedEurope PMCScholia
Smit L, de Vries-Smits AM, Bos JL, Borst J.; ''B cell antigen receptor stimulation induces formation of a Shc-Grb2 complex containing multiple tyrosine-phosphorylated proteins.''; PubMedEurope PMCScholia
Takahashi H, Arstikaitis P, Prasad T, Bartlett TE, Wang YT, Murphy TH, Craig AM.; ''Postsynaptic TrkC and presynaptic PTPσ function as a bidirectional excitatory synaptic organizing complex.''; PubMedEurope PMCScholia
Morrison KB, Tognon CE, Garnett MJ, Deal C, Sorensen PH.; ''ETV6-NTRK3 transformation requires insulin-like growth factor 1 receptor signaling and is associated with constitutive IRS-1 tyrosine phosphorylation.''; PubMedEurope PMCScholia
Patterson RL, van Rossum DB, Nikolaidis N, Gill DL, Snyder SH.; ''Phospholipase C-gamma: diverse roles in receptor-mediated calcium signaling.''; PubMedEurope PMCScholia
Qian X, Riccio A, Zhang Y, Ginty DD.; ''Identification and characterization of novel substrates of Trk receptors in developing neurons.''; PubMedEurope PMCScholia
Kim MS, Jeong J, Seo J, Kim HS, Kim SJ, Jin W.; ''Dysregulated JAK2 expression by TrkC promotes metastasis potential, and EMT program of metastatic breast cancer.''; PubMedEurope PMCScholia
Chardin P, Camonis JH, Gale NW, van Aelst L, Schlessinger J, Wigler MH, Bar-Sagi D.; ''Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2.''; PubMedEurope PMCScholia
Philo J, Talvenheimo J, Wen J, Rosenfeld R, Welcher A, Arakawa T.; ''Interactions of neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF), and the NT-3.BDNF heterodimer with the extracellular domains of the TrkB and TrkC receptors.''; PubMedEurope PMCScholia
Jin W, Yun C, Jeong J, Park Y, Lee HD, Kim SJ.; ''c-Src is required for tropomyosin receptor kinase C (TrkC)-induced activation of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway.''; PubMedEurope PMCScholia
Carpenter G, Ji Q.; ''Phospholipase C-gamma as a signal-transducing element.''; PubMedEurope PMCScholia
Lannon CL, Martin MJ, Tognon CE, Jin W, Kim SJ, Sorensen PH.; ''A highly conserved NTRK3 C-terminal sequence in the ETV6-NTRK3 oncoprotein binds the phosphotyrosine binding domain of insulin receptor substrate-1: an essential interaction for transformation.''; PubMedEurope PMCScholia
Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMedEurope PMCScholia
Lamballe F, Klein R, Barbacid M.; ''trkC, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3.''; PubMedEurope PMCScholia
Cargnello M, Roux PP.; ''Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.''; PubMedEurope PMCScholia
Hower AE, Beltran PJ, Bixby JL.; ''Dimerization of tyrosine phosphatase PTPRO decreases its activity and ability to inactivate TrkC.''; PubMedEurope PMCScholia
Werner P, Paluru P, Simpson AM, Latney B, Iyer R, Brodeur GM, Goldmuntz E.; ''Mutations in NTRK3 suggest a novel signaling pathway in human congenital heart disease.''; PubMedEurope PMCScholia
Robinson RC, Radziejewski C, Spraggon G, Greenwald J, Kostura MR, Burtnick LD, Stuart DI, Choe S, Jones EY.; ''The structures of the neurotrophin 4 homodimer and the brain-derived neurotrophic factor/neurotrophin 4 heterodimer reveal a common Trk-binding site.''; PubMedEurope PMCScholia
Salvesen GS, Duckett CS.; ''IAP proteins: blocking the road to death's door.''; PubMedEurope PMCScholia
Plotnikov A, Zehorai E, Procaccia S, Seger R.; ''The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation.''; PubMedEurope PMCScholia
Cseh B, Doma E, Baccarini M.; ''"RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway.''; PubMedEurope PMCScholia
Brown MD, Sacks DB.; ''Protein scaffolds in MAP kinase signalling.''; PubMedEurope PMCScholia
Gromnitza S, Lepa C, Weide T, Schwab A, Pavenstädt H, George B.; ''Tropomyosin-related kinase C (TrkC) enhances podocyte migration by ERK-mediated WAVE2 activation.''; PubMedEurope PMCScholia
Beltran PJ, Bixby JL, Masters BA.; ''Expression of PTPRO during mouse development suggests involvement in axonogenesis and differentiation of NT-3 and NGF-dependent neurons.''; PubMedEurope PMCScholia
Butte MJ, Hwang PK, Mobley WC, Fletterick RJ.; ''Crystal structure of neurotrophin-3 homodimer shows distinct regions are used to bind its receptors.''; PubMedEurope PMCScholia
Tchetchelnitski V, van den Eijnden M, Schmidt F, Stoker AW.; ''Developmental co-expression and functional redundancy of tyrosine phosphatases with neurotrophin receptors in developing sensory neurons.''; PubMedEurope PMCScholia
Dalva MB, McClelland AC, Kayser MS.; ''Cell adhesion molecules: signalling functions at the synapse.''; PubMedEurope PMCScholia
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA.; ''Mutations of the BRAF gene in human cancer.''; PubMedEurope PMCScholia
Huang EJ, Reichardt LF.; ''Neurotrophins: roles in neuronal development and function.''; PubMedEurope PMCScholia
Dean C, Dresbach T.; ''Neuroligins and neurexins: linking cell adhesion, synapse formation and cognitive function.''; PubMedEurope PMCScholia
McKay MM, Morrison DK.; ''Integrating signals from RTKs to ERK/MAPK.''; PubMedEurope PMCScholia
Kyriakis JM, Avruch J.; ''Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update.''; PubMedEurope PMCScholia
Roberts PJ, Der CJ.; ''Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.''; PubMedEurope PMCScholia
Cantwell-Dorris ER, O'Leary JJ, Sheils OM.; ''BRAFV600E: implications for carcinogenesis and molecular therapy.''; PubMedEurope PMCScholia
Coles CH, Mitakidis N, Zhang P, Elegheert J, Lu W, Stoker AW, Nakagawa T, Craig AM, Jones EY, Aricescu AR.; ''Structural basis for extracellular cis and trans RPTPσ signal competition in synaptogenesis.''; PubMedEurope PMCScholia
Roskoski R.; ''RAF protein-serine/threonine kinases: structure and regulation.''; PubMedEurope PMCScholia
Faux C, Hawadle M, Nixon J, Wallace A, Lee S, Murray S, Stoker A.; ''PTPsigma binds and dephosphorylates neurotrophin receptors and can suppress NGF-dependent neurite outgrowth from sensory neurons.''; PubMedEurope PMCScholia
Tognon C, Garnett M, Kenward E, Kay R, Morrison K, Sorensen PH.; ''The chimeric protein tyrosine kinase ETV6-NTRK3 requires both Ras-Erk1/2 and PI3-kinase-Akt signaling for fibroblast transformation.''; PubMedEurope PMCScholia
The intrinsic (Bcl-2 inhibitable or mitochondrial) pathway of apoptosis functions in response to various types of intracellular stress including growth factor withdrawal, DNA damage, unfolding stresses in the endoplasmic reticulum and death receptor stimulation. Following the reception of stress signals, proapoptotic BCL-2 family proteins are activated and subsequently interact with and inactivate antiapoptotic BCL-2 proteins. This interaction leads to the destabilization of the mitochondrial membrane and release of apoptotic factors. These factors induce the caspase proteolytic cascade, chromatin condensation, and DNA fragmentation, ultimately leading to cell death. The key players in the Intrinsic pathway are the Bcl-2 family of proteins that are critical death regulators residing immediately upstream of mitochondria. The Bcl-2 family consists of both anti- and proapoptotic members that possess conserved alpha-helices with sequence conservation clustered in BCL-2 Homology (BH) domains. Proapoptotic members are organized as follows:
1. "Multidomain" BAX family proteins such as BAX, BAK etc. that display sequence conservation in their BH1-3 regions. These proteins act downstream in mitochondrial disruption.
2. "BH3-only" proteins such as BID,BAD, NOXA, PUMA,BIM, and BMF have only the short BH3 motif. These act upstream in the pathway, detecting developmental death cues or intracellular damage. Anti-apoptotic members like Bcl-2, Bcl-XL and their relatives exhibit homology in all segments BH1-4. One of the critical functions of BCL-2/BCL-XL proteins is to maintain the integrity of the mitochondrial outer membrane.
Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
Synapses constitute highly specialized sites of asymmetric cell-cell adhesion and intercellular communication. Its formation involves the recruitment of presynaptic and postsynaptic molecules at newly formed contacts. Synapse assembly and maintenance invokes heterophilic presynaptic and postsynaptic transmembrane proteins that bind each other in the extracellular space and recruit additional proteins via their intracellular domains. Members of the cadherin and immunoglobulin (Ig) superfamilies are thought to mediate this function. Several molecules, including synaptic cell-adhesion molecule (SynCAM), N-cadherin, neural cell-adhesion molecule (NCAM), Eph receptor tyrosine kinases, and neuroligins and neurexins, have been implicated in synapse formation and maintenance (Dean & Dresbach 2006, Craig et al. 2006, Craig & Kang 2007, Sudhof 2008).
The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009). The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
Neurtrophin-3 (NTF3, also known as NT-3) is the main ligand for the neuronal receptor tyrosine kinase NTRK3 (TRKC) (Lamballe et al. 1991). NTRK3 is not activated by other member of the neurotrophin family (NGF, BDNF and NTF4) (Lamballe et al. 1991, Ip et al. 1993). Binding to the NTF3 homodimer induces dimerization of the NTRK3 (TRKC) receptor, so that the stoichiometry of the ligand:receptor complex is 2:2 (Philo et al. 1994). In the study by Philo et al., a recombinant human NTF3 was used with a recombinant extracellular region of NTRK3, but the origin of NTRK3 was not specified.
NTRK3 (TRKC), activated by NTF3 binding, trans-autophosphorylates on tyrosine residues in the intracellular domain (Urfer et al. 1995, Yuen and Mobley 1999, Huang and Reichardt 2001). Tyrosine residue Y516 of NTRK3 was directly shown to be autophosphorylated (Werner et al. 2014), while tyrosine residues Y705, Y709, Y710 and Y834 are predicted to be phosphorylated based on sequence similarity with NTRK2 (TRKB).
Kinase activity of NTRK3 (TRKC) is needed for tyrosine phosphorylation and activation of PLCG1 in response to NTF3 (NT-3) (Guiton et al. 1995, Marsh and Palfrey 1996). NTRK3-mediated phosphorylation sites on PLCG1 have not been determined but are predicted to involve four tyrosine residues whose phosphorylation is known to be required for the phospholipase activity of PLCG1: Y472, Y771, Y783 and Y1253.
Based on the accepted model of PLCgamma1 (PLCG1) signaling, although this has not been tested in the context of the NTRK3 (TRKC) receptor-mediated activation of PLCG1, phosphorylated, active, PLCG1 dissociates from the receptor tyrosine kinase and catalyzes formation of DAG and IP3 second messengers (Carpenter and Ji 1999). Activation of rat Ntrk3 by human NTF3 (NT-3) is known to result in tyrosine phosphorylation of rat Plcg1 and activation of DAG and IP3 signaling (Marsh and Palfrey 1996).
NTRK3, activated by NTF3 (NT-3), binds SHC1 isoforms p52 (SHC1-2) and p46 (SHC1-3), which function as activators of RAS signaling (Yuen and Mobley 1999).
NTRK3 (TRKC), activated by NTF3 (NT-3), phosphorylates the adaptor protein SHC1 on unknown tyrosine residue(s) (Gunn-Moore et al. 1997, Yuen and Mobley 1999).
SHC1, phosphorylated by NTRK3 (TRKC), binds GRB2. Based on studies of NTRK1 (TRKA) and NTRK2 (TRKB2) and evidence that RAS signaling is activated downstream of NTRK3 (Gunn-Moore et al. 1997, Yuen and Mobley 1999), GRB2 is shown in complex with RAS guanine nucleotide exchange factor SOS1.
Stimulation of NTRK3 (TRKC) by recombinant human NTF3 (NT-3) increases the amount of GTP-bound RAS (Marsh and Palfrey 1996). Activation of RAS targets MAPK3 (ERK1) and MAPK1 (ERK2) was shown to depend on SHC1-mediated recruitment of GRB2 to activated NTRK3 (Gunn-Moore et al. 1997, Yuen and Mobley 1999).
The PI3K complex, composed of the catalytic subunit PIK3CA and the regulatory subunit PIK3R1, co-immunoprecipitates with activated NTRK3. It is uncertain whether the interaction between NTRK3 and PI3K is direct or if adaptor protein(s) are involved (Yuen and Mobley 1999).
Activated wild-type NTRK3 (TRKC), as well as constitutively active ETV6-NTRK3 oncogene, a product of translocation between ETV6 and NTRK3 gene loci in congenital fibrosarcoma and cellular mesoblastic nephroma, are able to bind to adaptor protein IRS1 (Morrison et al. 2002, Lannon et al. 2004, Jin et al. 2008). Binding of IRS1 to NTRK3 is enhanced in the presence of SRC (Jin et al. 2008).
Activation of PI3K signaling downstream of NTRK3 (TRKC) is evident from PI3K-dependent activating phosphorylation of AKT in response to NTRK3 activity. SRC and IRS1 contribute to NTRK3-mediated induction of PI3K activity, but the exact mechanism is not known (Tognon et al. 2001, Jin et al. 2008).
In the absence of ligand, NTRK3 (TRKC) is cleaved by an unknown caspase. CASP3 (caspase-3) cleaves NTRK3 in vitro, but CASP3 inhibitors do not prevent NTRK3 cleavage in live cells. CASP8 (caspase-8) is unable to cleave NTRK3 in vitro. A general caspase inhibitor prevents NTRK3 cleavage in live cells (Tauszig-Delamasure et al. 2007).
NTRK3(496-641), the NTRK3 (TRKC) killer fragment (KF) binds to NELFB in the cytosol. NELFB (COBRA1) is known as a negative regulator of transcriptional elongation and a BRCA1 co-factor. NELFB is predominantly nuclear but is also found outside of the nucleus (Ichim et al. 2013).
The complex of NTRK3 (TRKC) killer fragment (KF) and NELFB (COBRA1) stimulates BAX activation through an unknown mechanism. This is followed by BAX-dependent cytochrome C release and apoptosome-dependent cell death (Ichim et al. 2013).
Receptor protein tyrosine phosphatases PTPRO and PTPRS (PTPsigma) are co-expressed with NTRK3 (TRKC) in a large portion of NTRK3 positive neurons. Recombinant PTPRO (Beltran et al. 2003, Hower et al. 2009, Tchetchelnitski et al. 2014) and PTPRS (Faux et al. 2007, Tchetchelnitski et al. 2014) are both able to bind NTRK3 and promote NTRK3 dephosphorylation, thus attenuating NTRK3 signaling. The precise mechanism has not been elucidated.
In addition to interaction between PTPRS and NTRK3 in-cis, extracellular domain of pre-synaptic PTPRS can bind in-trans to extracellular domain of post-synaptic NTRK3, contributing to synapse formation (Takahashi et al. 2011, Coles et al. 2014).
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1. "Multidomain" BAX family proteins such as BAX, BAK etc. that display sequence conservation in their BH1-3 regions. These proteins act downstream in mitochondrial disruption.
2. "BH3-only" proteins such as BID,BAD, NOXA, PUMA,BIM, and BMF have only the short BH3 motif. These act upstream in the pathway, detecting developmental death cues or intracellular damage. Anti-apoptotic members like Bcl-2, Bcl-XL and their relatives exhibit homology in all segments BH1-4. One of the critical functions of BCL-2/BCL-XL proteins is to maintain the integrity of the mitochondrial outer membrane.
interactions at
synapsesThe importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
Annotated Interactions
In addition to interaction between PTPRS and NTRK3 in-cis, extracellular domain of pre-synaptic PTPRS can bind in-trans to extracellular domain of post-synaptic NTRK3, contributing to synapse formation (Takahashi et al. 2011, Coles et al. 2014).