Neuregulin-ERBB signaling in the nervous system and neuropsychiatric diseases

Abstract

Neuregulins (NRGs) comprise a large family of growth factors that stimulate ERBB receptor tyrosine kinases. NRGs and their receptors, ERBBs, have been identified as susceptibility genes for diseases such as schizophrenia (SZ) and bipolar disorder. Recent studies have revealed complex Nrg/Erbb signaling networks that regulate the assembly of neural circuitry, myelination, neurotransmission, and synaptic plasticity. Evidence indicates there is an optimal level of NRG/ERBB signaling in the brain and deviation from it impairs brain functions. NRGs/ERBBs and downstream signaling pathways may provide therapeutic targets for specific neuropsychiatric symptoms.

Figure 1. NRG-ERBB canonical signaling

NRGs are encoded by six individual genes NRG1-6 (Carraway et al., 1997; Chang et al., 1997; Harari et al., 1999; Howard et al., 2005; Kanemoto et al., 2001; Kinugasa et al., 2004; Uchida et al., 1999; Watanabe et al., 1995; Zhang et al., 1997). NRG1 has six Types (I-VI), each with a distinct N-terminus, Ig domain and/or cysteine-rich domain. NRG1 Type I was identified as heregulin, neu differentiation factor (NDF), and ARIA (acetyl choline receptor inducing activity) (Holmes et al., 1992; Peles et al., 1992). Type II and III were identified as GGF (for ‘glial growth factor’) (Lemke and Brockes, 1984) and SMDF (for ‘sensory and motor neuron derived factor’), respectively (Ho et al., 1995). NRG5 is also called tomoregulin or TMEFF1 (transmembrane protein with EGF-like and two follistatin-like domains 1); whereas NRG6 could be referred as neuroglycan C, CSPG5 (chondroitin sulfate proteoglycan 5) or CALEB (chicken acidic leucine-rich EGF-like domain containing brain protein). NRGs are synthesized as transmembrane proteins and display an extracellular EGF-like domain, which is essential for ERBB receptor binding. ERBB tyrosine kinases have four members: EGFR/ERBB1, ERBB2, ERBB3 and ERBB4, each of which has a unique group of ligands except ERBB2 whose ligand remains unknown. ERBB3 kinase activity is impaired (indicated by a cross). Ligand binding causes dimerization and activation of ERBBs, and subsequent phosphorylation of the intracellular domains (ICDs), and creates docking sites for adapter proteins including Grb2 and Shc for Erk activation and for p85 for PI3K activation, and for Src kinases, Pyk2 and Cdk5, and PLCγ. Ligands and ERBBs are color-matched, those in light blue bind both to EGFR and ERBB4 and those in red bind both to ERBB3 and ERBB4. Abbreviations. AREG, amphiregulin; BTC, β-cellulin; CSPG5, chondroitin sulfate proteoglycan 5; CTF, C-terminal fragment; CALEB, chicken acidic leucine-rich EGF-like domain containing brain protein; ECD, extracellular domain; EGF, epidermal growth factor; EGFR, EGF receptor; EPGN, epigen; EPR, epiregulin; Grb2, growth factor receptor-bound protein 2; HBEGF, heparin-binding EGF-like growth factor; ICD, intracellular domain; Ig, immunoglobin; LDLR-B, LDL receptor class B; Shc, SRC-homology domain-containing; Stat5, signal transducer and activator of transcription 5; TGFα, transforming growth factor-α.; TMEFF1, transmembrane protein with EGF-like and two follistatin-like domains 1.

Figure 2. Nrg1 non-canonical signaling

Nrg1 is cleaved by extracellular proteases including BACE1 (or disintegrin or ADAM) (Hu et al., 2006; Luo et al., 2011; Savonenko et al., 2008; Velanac et al., 2012; Willem et al., 2006) and neuropsin to release soluble, mature Nrg1 that contains the EGF-like domain (Tamura et al., 2012). Soluble Nrg1 binds and activates Erbb kinases to activate the canonical pathways although soluble Nrg1-induced endocytosis of GABA-A receptor α1 was independent of Erbb4 kinase (Mitchell et al., 2013) (Box I) (see Figure 1). Pro-Nrg1 and mature Type III may function as receptor of soluble, extracellular domain of Erbb4 to initiate backward signaling (Hancock et al., 2008; Zhong et al., 2008) (Box II). Transmembrane Nrg1s could directly interact with transmembrane Erbb4 or other proteins to signal in a cell-adhesion dependent manner, some of which may be kinase-independent (Chen et al., 2010a; Chen et al., 2008; Del Pino et al., 2013; Fazzari et al., 2010; Krivosheya et al., 2008)(Box III). Cleavage of Nrg1- or Erbb4-C-terminal fragments (CTFs) give rise to respective intracellular domains (ICDs) that are believed to signal into the nucleus (Bao et al., 2004; Bao et al., 2003) (Lee et al., 2002; Ni et al., 2001; Sardi et al., 2006) (Box IV and V).

Figure 3. Nrg1 and Erbb4 in neural circuitry assembly

A, Regulation of migration and differentiation of GABAergic interneurons, including development of neuronal processes and synapse formation. B, Schematic diagram of inhibitory and excitatory circuitries. C, Cellular mechanisms of Nrg1 and Erbb4 in forming inhibitory and excitatory synapses onto inhibitory and excitatory neurons. tmNrg1, transmembrane Nrg1 including Type III Nrg1 and proNrg1; sNrg, soluble Nrg1. See text for details.

Figure 4. Nrg1 Type III in Schwann cell myelination

A, Schematic depiction of Schwann cells and their precursors (in blue) stimulated by axons (in cross section, brown) through all stages of the Schwann cell lineage, i.e. from the proliferating precursors (left) to myelinating Schwann cells (right). Glial Erbb receptors (green) integrate Nrg1 Type III (red) signals from the axon surface, generating intracellular second messenger signals as surrogates of axon size. Thus threshold levels of axonal NRG1 initiate myelination once the axon caliber measures about 1 μm. B, Transgenic overexpression of Nrg1 Type III increases the density of this ligand on the axon surface causing significant hypermyelination, without increase of axon caliber.

Figure 5. Nrg1 in remyelination of the PNS after nerve injury

In intact nerves, axonal Nrg1 Type III controls myelination and inhibits Nrg1 Type I expression by Schwann cells. Following Wallerian degeneration, Schwann cells are detached and the axonal Nrg1 Type III signal is lost. At this stage, expression of Nrg1 Type I by Schwann cells is ‘de-repressed’ and promotes Schwann cell differentiation and remyelination in a transient autocrine/paracrine signaling loop (from Stassart et al., 2013 with permission to be obtained).

Figure 6. Nrg1 in neurotransmission and synaptic plasticity

A, B, Schematic diagrams of circuitry in the CA1 region of the hippocampus. Ca, Nrg1 activates Erbb4 in interneurons and promotes GABA release by altering excitability and/or vesicle release to suppress LTP. Cb, Nrg1 inhibits Src activation in pyramidal neurons to suppress LTP. Cc, Nrg1 stimulates dopamine release in the hippocampus and suppresses LTP in a manner that requires D4R. Cd, Transmembrane Nrg1 (tmNrg1) such as Type III initiates backward signaling to promote presynaptic α7-AChR expression which is required for converting short term potentiation (STP) to LTP at cortico-BLA synapses. See text for details.

Figure 7. NRG1, NRG3 and ERBB4 SNPs and association with psychiatric disorders

Chromosome location, size, and the total number of SNPs of NRG1, NRG3 and ERBB4 are described under each gene name. Each oval represents a case study. Colors indicate intronic or exonic SNPs with or without functional association, or SNPs associated with bipolar disorder. *, SNPs implicated by GWAS. For Nrg1, 1, rs73235619/Snp8nrg221132; 2, rs35753505/SNP8NRG221533; 3, rs4623364/SNP8NRG222662; 4, rs62510682/SNP8NRG241930; 5, rs6994992/SNP8NRG243177; 6, rs7014762; 7, SNP8NRG433E1006; 8, rs4316112; 9, rs3924999; 10, rs2439272; 11, rs10095694; 12, rs16879809; 13, rs10503929; and 14, rs74942016. For Nrg3, 1, rs10748842. For ErbB4, 1, rs7598440; 2, rs1851196; and 3, rs3748962.

Figure 8. Inverted U-curve illustrating the relationship between NRG1/ERBB level and activity and cognitive/behavioral performance

Y axis shows cognitive/behavioral performance; darker color indicates poorer performance. X axis shows NRG1 and ERBB level and activity with 1 as normal. Green shade indicates the optimal range.