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.
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