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Mice Dispense With Neuregulin/ErbB Pathway in CNS Myelination

22 September 2008. The schizophrenia candidate risk gene, neuregulin (NRG1), encodes a neurotrophic growth factor involved in multiple developmental pathways and processes implicated in the disease, including neuronal migration and axonal path finding, as well as synaptic function. In the peripheral nervous system, neuregulin controls the development of Schwann cells and the myelination of axons. Defects in central nervous system myelination are widely noted in people with schizophrenia, so it seems reasonable to conjecture that changes in NRG1 might be involved there, too.

But not so fast. Some new data from Markus Schwab and Klaus Armin Nave at the Max Planck Institute of Experimental Medicine in Goettingen, Germany, suggest otherwise. In a study published in the August 28 issue of Neuron, the researchers show that oligodendrocyte development and myelination proceeds normally on CNS neurons in brain-specific neuregulin or ErbB knockout mice. The results reveal a surprising divergence of function for the Nrg1/ErbB pathways between Schwann cells in the periphery and oligodendrocytes in the CNS. If the same phenomenon replicates in people, it suggests that any pathological effects of Nrg1/ErbB pathway disruption may stem from causes other than major changes in CNS myelination.

The exact roles of Nrg1 or ErbB proteins on brain development have been difficult to study in vivo, because mice lacking either gene die before birth. Hemizygous NRG1 knockout mice, on the other hand, survive normally, and display a hypomyelination of peripheral neurons. However, when first authors Bastian Brinkmann and Amit Agarwal looked at myelination in several CNS locations in the mice, they were surprised to find no reduction in myelin thickness or alteration in myelin structure. In further studies, they used brain- and stage-specific expression systems to look at the effects of knocking out or overexpressing Nrg1 in CNS neurons at different developmental stages. They found no evidence for any effects of Nrg1 on oligodendrocyte development or function, or myelin formation or maintenance in the CNS throughout life.

In the CNS, Nrg1 stimulates myelination in its membrane-bound type III form, which is expressed on the surface of axons. Other splice forms of neuregulin can be cleaved at the cell surface by the β-secretase enzyme Bace1, releasing a soluble factor that acts in a paracrine fashion to stimulate myelination. To rule out astrocyte-derived soluble neuregulin as a stimulator of myelination, the researchers knocked out NRG1 in brain embryonic precursor cells, which resulted in mice with no Nrg1 in any brain cells. Those mice still showed normal myelination of CNS neurons.

Similar results were obtained when the investigators knocked out the major neuregulin receptors ErbB3 and ErbB4 specifically in oligodendrocytes. Mice lacking both receptors, and thus devoid of Nrg1 signaling in myelinating cells, showed normal CNS myelination.

Together, the results suggest that neuregulin/ErbB signaling is dispensable for CNS myelination in vivo, the authors conclude. This result is contrary to previous in vitro work showing that Nrg1 is required for oligodendrocyte development and survival (e.g., see Canoll et al., 1996; Vartanian et al., 1999). By way of explanation, the authors speculate that in vitro, Nrg1/ErbB pathway activation might compensate for the lack of electrical activity in axons, which normally stimulates myelination in vivo. The idea that Nrg1 can stimulate CNS myelination under some circumstances is supported by their observation that overexpression of Nrg1 type I or type III in neurons of transgenic mice enhanced early myelination during development. This occurred without any change in the number of oligodendroctyes. Overexpression of Nrg1 did not affect the extent of remyelination of mature CNS neurons after injury, however.

For reasons that are less clear, the new results also differ from previous in vivo studies showing cortical hypomyelination in mice lacking Nrg1 type III (Taveggia et al., 2008) and a CNS myelination defect induced by expression of a dominant negative ErbB4 in oligodendroctyes (see SRF related news story).

The authors conclude, “Our data suggest that CNS evolution has made vertebrate oligodendrocytes independent from NRG1, presumably the ancestral signal on axons that is necessary and sufficient for myelination by Schwann cells. Perhaps, a simple system (represented by NRG1 type III/ErbB signaling to Schwann cells) has been superseded in the CNS by a complex system that includes neuronal activity as a myelination signal.”

In people with schizophrenia, white matter anomalies have been documented. “While altered NRG1 expression levels could be a plausible cause and ‘missing link’ to epidemiological data, our observation in mutant mice suggests otherwise,” the authors write. “Although it is difficult to make predictions across species, these data suggest that small alterations in NRG1 expression, as predicted for the Nrg1 at risk haplotype in humans, is highly unlikely to explain the white matter abnormalities independently documented in schizophrenia patients.” Nonetheless, they conclude, some of the mouse mutants they have developed “will be useful to study other schizophrenia-relevant functions in vivo, such as the role of the Nrg1 gene in synaptic plasticity and cognitive functions.”—Pat McCaffrey.

Reference:
Brinkmann BG, Agarwal A, Sereda MW, Garratt AN, Müller T, Wende H, Stassart RM, Nawaz S, Humml C, Velanac V, Radyushkin K, Goebbels S, Fischer TM, Franklin RJ, Lai C, Ehrenreich H, Birchmeier C, Schwab MH, Nave KA. Neuregulin-1/ErbB signaling serves distinct functions in myelination of the peripheral and central nervous system. Neuron. 2008 Aug 28;59(4):581-95. Abstract

Comments on News and Primary Papers
Comment by:  David Talmage
Submitted 22 September 2008
Posted 22 September 2008

To the extent that animal models can represent the human condition, this paper argues against a direct connection between changes in Nrg1/ErbB function and the glial hypothesis that is based on postmortem evidence implicating Nrg1/ErbB3 signaling in the etiology of schizophrenia. However, there is a clear difference from the results in this paper with both data from Taveggia, Salzer et al. (on CNS myelination in Nrg1 heterozygotes) and Corfas and colleagues (in animals in which ErbB function is blocked in oligodendrocytes) that needs resolution before any real conclusion can be made. At this point, I think the basic conclusion is that we have a lot more precise (at the cellular level) work to do before we can make really strong predictions on which disease-associated phenotypes relate to disruptions in normal Nrg1/ErbB signaling.

View all comments by David Talmage

Comments on Related News


Related News: Neuregulin and ErbB4 Mutant Mice Reveal Myelin and Synaptic Deficits

Comment by:  Daniel StewartKenneth Davis
Submitted 3 May 2007
Posted 3 May 2007

Comment by Daniel Stewart and Kenneth Davis
The Corfas results are intriguing. Their findings confirm much of what we have either found or suspect in schizophrenia relating to white matter involvement. Demonstrations of OLIG2 interactions with ErbB4 in the cortex and with CNP in the striatum in schizophrenia from our team (Georgieva et al., 2006) fit well with this investigation in providing evidence for a link between a variety of potential etiologic oligodendrocyte-related mechanisms in schizophrenia. While in our study, we did not find interaction with NRG1 and OLIG2, it is important to note that differential expression of NRG1 might be found only at certain points in the timeline of disease development. Other recent support from our team for white matter involvement in schizophrenia comes from an investigation in which an SNP associated with CNP was found to be significantly correlated with schizophrenia (Peirce et al., 2006). Interestingly, Corfas’s group reports that when ErbB signaling is abolished in oligodendrocytes, myelin structure appears normal, but the myelin sheath is significantly thinner. This is in line with some of the ultrastructural findings of Uranova’s group and in rodent studies looking at MAG-deficient mice (both reviewed in Davis et al., 2003)—another downregulated myelin-related gene found in brains of schizophrenia patients.

Reductions in oligodendrocyte number on the order of 20 percent have been demonstrated in the brains of schizophrenia patients (Hof et al., 2002). Although this finding does not precisely parallel the findings in this investigation, the authors’ adroitly point out that this may be because the abnormalities they induced were during early oligodendrocyte and myelin expression, while it is possible that the abnormalities seen in the brains of schizophrenia patients occur relatively later in development, more likely during the second large wave of cortical myelination at the end of the second decade of life. The authors also point out that “defects in ErbB signaling in different cell types may contribute to different aspects of psychiatric symptoms.” This might also be the case in schizophrenia, giving rise to the myriad presentations of the disease, as might the fact that expression of both NRG1 and ErbB4 are susceptible to environmental insult.

Other important similarities between the authors’ findings and schizophrenia include that, even in light of these myelin abnormalities, gross brain volumes, as well as several other measures, remained normal. This buttresses the idea that in schizophrenia, myelin abnormalities might be at the root of the often unimpressive brain changes noted in schizophrenia on gross structural imaging. And finally, although speculative, the authors do note an intriguing set of behavioral abnormalities, some of which could mimic the social isolation and poor relatedness of schizophrenia, which is particularly remarkable given the increased susceptibility to amphetamines and the trends seen in DAT, D1, and D2 expression in this investigation.

Corfas’s findings are indeed exciting, and we commend his team on an eloquently designed and implemented investigation.

View all comments by Daniel Stewart
View all comments by Kenneth Davis

Related News: Neuregulin and ErbB4 Mutant Mice Reveal Myelin and Synaptic Deficits

Comment by:  Akira Sawa, SRF Advisor
Submitted 4 May 2007
Posted 4 May 2007

Neuregulin1 (NRG1) is the most promising risk factor for schizophrenia, and the study of the signaling of NRG1 and its receptor ErbB4 is very important in understanding the pathophysiology of the disease. Like other promising risk factors for schizophrenia, NRG1/ErbB4 is multifunctional with many molecular isoforms. NRG1/ErbB signaling plays a role both before and after birth. Furthermore, ErbB4 is expressed not only in neurons but also in other types of cells, such as oligodendrocytes.

To address context-dependent functions one by one, dominant-negative transgenic mice can be very useful. The advantage of dominant-negative transgenics is that we can knock down the endogenous function of our target molecules (in this work, ErbB4) in a temporally and spatially specific manner by utilizing a well-characterized promoter. In this outstanding study by Corfas and colleagues, they used the CNP promoter that confirms dominant-negative ErbB4 selectively in oligodendrocytes (but not in astrocytes and neurons) only after birth. This approach will be very useful in schizophrenia research.

The remarkable finding is that they observed alterations in dopamine-mediated neuronal networks and associated behaviors by disturbing NRG1/ErbB4 selectively in cells of oligodendrocyte lineage. Three important paradigms for schizophrenia (white matter pathology, dopamine, and a susceptibility gene) converge in this paper, and in this sense, I find it very exciting.

View all comments by Akira Sawa

Related News: Neuregulin and ErbB4 Mutant Mice Reveal Myelin and Synaptic Deficits

Comment by:  Mary Reid
Submitted 3 May 2007
Posted 5 May 2007

Does the effect of NRG1/ErbB4 signaling on myelination occur downstream of purinergic signaling? Fields suggests that adenosine is of primary importance in regulating early development of OPCs, where it stimulates differentiation and myelination (Fields, 2006). It's of interest that cAMP stimulates expression of neuregulin and cAMP levels in the lung are decreased in A2A adenosine receptor (22q11.2)-deficient mice (Tokita et al., 2001; Nadeem et al., 2007). Do you see reduced neuregulin levels in 22q11 deletion syndrome? Of particular interest is the study by Desai and colleagues reporting that signaling via the adenosine A2A receptor downregulates thrombospondin 1 (Desai et al., 2005). Perhaps overexpression of thrombospondin 1 may help explain the occular abnormalities in this syndrome (Wu et al., 2006; Forbes et al., 2007; Stalmans, 2005). Thrombospondins are also involved in synaptogenesis (Christopherson et al., 2005).

References:

Fields RD. Nerve impulses regulate myelination through purinergic signalling. Novartis Found Symp. 2006;276:148-58; discussion 158-61, 233-7, 275-81.

Tokita Y, Keino H, Matsui F, Aono S, Ishiguro H, Higashiyama S, Oohira A. Regulation of neuregulin expression in the injured rat brain and cultured astrocytes. J Neurosci. 2001 Feb 15;21(4):1257-64.

Nadeem A, Fan M, Ansari HR, Ledent C, Mustafa SJ. Enhanced airway reactivity and inflammation in A2A adenosine receptor deficient allergic mice. Am J Physiol Lung Cell Mol Physiol. 2007 Feb 9; [Epub ahead of print]

Desai A, Victor-Vega C, Gadangi S, Montesinos MC, Chu CC, Cronstein BN. Adenosine A2A receptor stimulation increases angiogenesis by down-regulating production of the antiangiogenic matrix protein thrombospondin 1. Mol Pharmacol. 2005 May;67(5):1406-13. Epub 2005 Jan 26. Comment in: Mol Pharmacol. 2005 May;67(5):1385-7.

Wu Z, Wang S, Sorenson CM, Sheibani N. Attenuation of retinal vascular development and neovascularization in transgenic mice over-expressing thrombospondin-1 in the lens. Dev Dyn. 2006 Jul;235(7):1908-20.

Forbes BJ, Binenbaum G, Edmond JC, Delarato N, McDonald-McGinn DM, Zackai EH. Ocular findings in the chromosome 22q11.2 deletion syndrome. J AAPOS. 2007 Apr;11(2):179-182. Epub 2006 Nov 30.

Stalmans I. Role of the vascular endothelial growth factor isoforms in retinal angiogenesis and DiGeorge syndrome. Verh K Acad Geneeskd Belg. 2005;67(4):229-76.

Christopherson KS, Ullian EM, Stokes CC, Mullowney CE, Hell JW, Agah A, Lawler J, Mosher DF, Bornstein P, Barres BA. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell. 2005 Feb 11;120(3):421-33. Comment in: Cell. 2005 Feb 11;120(3):292-3.

View all comments by Mary Reid

Related News: Neuregulin and ErbB4 Mutant Mice Reveal Myelin and Synaptic Deficits

Comment by:  Patricia Estani
Submitted 6 May 2007
Posted 6 May 2007
  I recommend the Primary Papers