Intramembranous Valine Linked to Schizophrenia Is Required for Neuregulin 1 Regulation of the Morphological Development of Cortical Neurons

Chen, Yachi; Hancock, Melissa L.; Role, Lorna W.; Talmage, David A.

doi:10.1523/jneurosci.0605-10.2010

Cited by 64 publications

(75 citation statements)

References 39 publications

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“…It is currently unclear as to the reason for the slowed rate of axon regeneration: in the absence of NRG1, less proregenerative factors such as neurotrophins may be produced by SCs [55]. Alternatively, NRG1 may act in a cell-autonomous manner to promote axon outgrowth, as observed in some CNS neurons [89].…”

Section: Endogenous Nrg1 Is Required For Nerve Repairmentioning

confidence: 99%

The Role of Neuregulin-1 In the Response To Nerve Injury

Fricker

Bennett

2011

Future Neurol.

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Axons and Schwann cells exist in a highly interdependent relationship: damage to one cell type invariably leads to pathophysiological changes in the other. Greater understanding of communication between these cell types will not only give insight into peripheral nerve development, but also the reaction to and recovery from peripheral nerve injury. The type III isoform of neuregulin-1 (NRG1) has emerged as a key signaling factor that is expressed on axons and, through binding to erbB2/3 receptors on Schwann cells, regulates multiple phases of their development. In adulthood, NRG1 is dispensable for the maintenance of the myelin sheath; however, this factor is required for both axon regeneration and remyelination following nerve injury. The outcome of NRG1 signaling depends on interactions with other pathways within Schwann cells such as Notch, integrin and cAMP signaling. In certain circumstances, this signaling pathway may be maladaptive; for instance, direct binding of Mycobacterium leprae onto erbB2 receptors produces excessive activation and can actually promote demyelination. Attempts to modulate this pathway in order to promote nerve repair will therefore need to give consideration to the exact isoform used, as well as how it is processed and the context in which it is presented to the Schwann cell. Keywordsneuregulin-1; neuropathy; peripheral nerve injury; regeneration; remyelination; repair; Schwann cell Peripheral nerve injury causes significant morbidity and reduced quality of life as a consequence of weakness, sensory loss and neuropathic pain. In total, 6% of the elderly population suffer from peripheral neuropathy [1], which can be caused by metabolic diseases such as diabetes, inherited genetic disorders such as Charcot-Marie-Tooth disease, infectious and inflammatory disorders including Guillan-Barré syndrome and traumatic injury to the nerve (which alone effects up to 300,000 people in Europe per year [1,2]). In contrast to the CNS, peripheral nerves have a significant regenerative capacity [3]; however, in patients, regeneration and the clinical outcome are often poor. Axons regenerate at a rate of approximately 1 mm per day, depending on the site of the lesion. There may be a delay of months if not years before the target zone is re-innervated, and by this time, the target organ and supporting cells may have irreversibly changed, becoming much less receptive to reinnervation. The current approaches to peripheral nerve repair following nerve transection are either to surgically suture the nerve or to bridge the gap between the two cut ends. Financial & competing interests disclosureThe authors have no other rel evant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Europe PMC Funders Group NRGs & the PNSNRGs Neuregulins are a family of growth factors en...

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Section: Endogenous Nrg1 Is Required For Nerve Repairmentioning

confidence: 99%

The Role of Neuregulin-1 In the Response To Nerve Injury

Fricker

Bennett

2011

Future Neurol.

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“…Although Chen et al (2010) do not clarify whether this difference is statistically significant, these experiments suggest that a small but considerable amount of WT Nrg1 was processed in absence of exogenous ErbB4 stimulation. As the authors subsequently claim that type III Nrg1 function is ErbB4 independent, it would be important to clarify this issue.Next, Chen et al (2010) tried to rescue the dendritic and axonal phenotype in type III Nrg1-null neurons by expressing WT or mutant forms of type III Nrg1 in vitro. They found that both residues V321/V322 and K329/Q330, which are required for type III Nrg1 cleavage and nuclear translocation, were necessary to rescue the dendritic phenotype.…”

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confidence: 64%

“…Recently, it was shown that Nrg1/ErbB4 forward signaling promotes the formation of inhibitory circuits in the cortex (Fazzari et al, 2010). Chen et al (2010) show that Nrg1 reverse signaling is important for the development of the dendritic arbor of pyramidal neurons (PNs).To address the function of type III Nrg1 in PNs in vivo, the authors compared the morphology of dendritic arbor of neurons in type III Nrg1-deficient and wild-type (WT) mice. The histological analysis of mutant and control brains revealed that the total length and number of branches of basal dendrites were greatly reduced in type III Nrg1-deficient versus WT neurons.…”

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confidence: 99%

“…Mimicking the in vivo data, the type III Nrg1 mutant neurons showed a clear reduction in dendritic development in vitro. In addition, the axonal length, but not the axonal branching, was reduced in type III Nrg1-deficient neurons.To elucidate the molecular mechanisms involved in type III NRG1 function in the development of dendrites and axons, Chen et al (2010) verified that Nrg1 reverse signaling occurs in cortical cultures by showing that ErbB4 binding stimulated translocation of NRG1-ICD to the nucleus and activated transcription of a luciferase reporter gene. Furthermore, they found mutations in the intracellular portion of Nrg1 (V321A/V322A and K329A/Q330A) that abolished the transcriptional activation.…”

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confidence: 99%

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Nrg1 Reverse Signaling in Cortical Pyramidal Neurons

Pedrique

Fazzari²

2010

J. Neurosci.

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Review of Chen et al.Schizophrenia is a severe neurological disorder characterized by psychotic symptoms, emotional distress, and cognitive deficits. It results from an amalgam of genetic, developmental, and environmental factors. In the last decade, several studies identified Nrg1 and its receptor ErbB4 as major schizophrenia-risk genes (Stefansson et al., 2002;Norton et al., 2006). Moreover, behavioral studies on different Nrg1 and ErbB4 mutant mice revealed various endophenotypes that are believed to be useful for modeling schizophrenia in mice (e.g., hyperactivity in response to novelty, hypersensitivity to psychostimulants, and deficits in working memory tasks). Similar phenotypes were shown in mice expressing mutated BACE-1 (the extracellular Nrg1-cleavage enzyme) (Savonenko et al., 2008) or Aph1B/C-␥-secretase (the Nrg1 intracellular proteolytic enzyme) (Dejaegere et al., 2008). Together, these findings suggest that perturbed Nrg1 signaling leads to functional deficits that correlate with schizophrenia. Nonetheless, Nrg1 and ErbB4 mutants do not display overt morphological defects in the brain and the precise role of Nrg1/ ErbB4 signaling in the nervous system remains elusive.In addition to canonical forward signaling via ErbB family receptors, the membrane-bound form of Nrg1 can also activate reverse signaling. Upon synaptic activation or receptor binding, membraneassociated type III Nrg1 is cleaved by ␥-secretase to release the intracellular domain (NRG1-ICD), which translocates to the nucleus where it regulates gene expression (Bao et al., 2003(Bao et al., , 2004. Recently, it was shown that Nrg1/ErbB4 forward signaling promotes the formation of inhibitory circuits in the cortex (Fazzari et al., 2010). Chen et al. (2010) show that Nrg1 reverse signaling is important for the development of the dendritic arbor of pyramidal neurons (PNs).To address the function of type III Nrg1 in PNs in vivo, the authors compared the morphology of dendritic arbor of neurons in type III Nrg1-deficient and wild-type (WT) mice. The histological analysis of mutant and control brains revealed that the total length and number of branches of basal dendrites were greatly reduced in type III Nrg1-deficient versus WT neurons. Because axon length could not be measured efficiently in vivo, the authors used primary cortical cultures. Mimicking the in vivo data, the type III Nrg1 mutant neurons showed a clear reduction in dendritic development in vitro. In addition, the axonal length, but not the axonal branching, was reduced in type III Nrg1-deficient neurons.To elucidate the molecular mechanisms involved in type III NRG1 function in the development of dendrites and axons, Chen et al. (2010) verified that Nrg1 reverse signaling occurs in cortical cultures by showing that ErbB4 binding stimulated translocation of NRG1-ICD to the nucleus and activated transcription of a luciferase reporter gene. Furthermore, they found mutations in the intracellular portion of Nrg1 (V321A/V322A and K329A/Q330A) that abolished the transcriptional activa...

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“…Gal4-VP16 (GV) transcriptional activator was fused to the C terminus of full-length mouse NRG1 type III WT or NRG1 type III Val/Leu (40,41). PC12 cells were transfected with NRG1-III-GV and reporter constructs containing five clustered Gal4-dependent upstream-activating sequences driving firefly luciferase expression upon GV activity, thus measuring nuclear translocation of ICD-GV (Fig.…”

Section: Nrg1 Cleavage and Nuclear Translocation Assay-thementioning

confidence: 99%

Proteolytic Processing of Neuregulin 1 Type III by Three Intramembrane-cleaving Proteases

Fleck¹,

Voß²,

Brankatschk

et al. 2016

Journal of Biological Chemistry

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Numerous membrane-bound proteins undergo regulated intramembrane proteolysis. Regulated intramembrane proteolysis is initiated by shedding, and the remaining stubs are further processed by intramembrane-cleaving proteases (I-CLiPs). Neuregulin 1 type III (NRG1 type III) is a major physiological substrate of ␤-secretase (␤-site amyloid precursor proteincleaving enzyme 1 (BACE1)). BACE1-mediated cleavage is required to allow signaling of NRG1 type III. Because of the hairpin nature of NRG1 type III, two membrane-bound stubs with a type 1 and a type 2 orientation are generated by proteolytic processing. We demonstrate that these stubs are substrates for three I-CLiPs

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Intramembranous Valine Linked to Schizophrenia Is Required for Neuregulin 1 Regulation of the Morphological Development of Cortical Neurons

Cited by 64 publications

References 39 publications

The Role of Neuregulin-1 In the Response To Nerve Injury

The Role of Neuregulin-1 In the Response To Nerve Injury

Nrg1 Reverse Signaling in Cortical Pyramidal Neurons

Proteolytic Processing of Neuregulin 1 Type III by Three Intramembrane-cleaving Proteases

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