Comment by Gabriel Corfas, Kristine Roy, and Suzhen Chen
Over the last decade, evidence implicating the growth factor neuregulin 1 (NRG1) and its receptors, the erbB tyrosine kinases, in myelination of the peripheral nervous system has been accumulating. The early studies examined the consequences of loss of NRG1-erbB function. For example, Garratt et al. (2000) showed that ablation of erbB2 in Schwann cells results in reductions of the number of Schwann cell precursors in the developing nerve and hypomyelination of sciatic nerve axons in the adult. Now, a paper by Nave's group (Michailov et al., 2004) has extended these findings by examining the outcome of both reductions and increases of NRG1-erbB signaling on myelin formation. As expected from the preceding evidence, this study found that reduction in NRG1 or erbB2 expression results in hypomyelination. The more surprising finding in this study is that overexpression of NRG1 in axons leads to increased myelin thickness in the sciatic nerve. These results indicate that NRG1 is part of the signaling mechanisms by...  Read more

Comment by Gabriel Corfas, Kristine Roy, and Suzhen Chen
Over the last decade, evidence implicating the growth factor neuregulin 1 (NRG1) and its receptors, the erbB tyrosine kinases, in myelination of the peripheral nervous system has been accumulating. The early studies examined the consequences of loss of NRG1-erbB function. For example, Garratt et al. (2000) showed that ablation of erbB2 in Schwann cells results in reductions of the number of Schwann cell precursors in the developing nerve and hypomyelination of sciatic nerve axons in the adult. Now, a paper by Nave's group (Michailov et al., 2004) has extended these findings by examining the outcome of both reductions and increases of NRG1-erbB signaling on myelin formation. As expected from the preceding evidence, this study found that reduction in NRG1 or erbB2 expression results in hypomyelination. The more surprising finding in this study is that overexpression of NRG1 in axons leads to increased myelin thickness in the sciatic nerve. These results indicate that NRG1 is part of the signaling mechanisms by which axons regulate the thickness of the myelin sheet produced by Schwann cells. Interestingly, this hypermyelination occurred only with overexpression of one NRG1 isoform, type III NRG1, which contains a cysteine-rich domain, but not with type I NRG1, which contains an Ig domain.

It is important to note that the roles of NRG1-erbB signaling in peripheral nerves are not confined to myelin-producing Schwann cells. We recently reported (Chen et al., 2003) that NRG1-erbB signaling is critical for interactions between unmyelinated axons and non-myelinating Schwann cells. We found that blockade of erbB signaling in non-myelinating Schwann cells results in a progressive peripheral neuropathy with a late-onset degeneration of selected populations of primary sensory neurons. These results indicate that NRG1-erbB signaling in some peripheral glial cells is important for long-term survival of their associated neurons.

We believe that the next important questions regarding the roles of NRG1-erbB signaling in neuron-glia interactions lie in the central nervous system, where the roles of these molecules are much less understood. The studies discussed above raise the question whether this signaling pathway is important for myelination in the brain. Moreover, the possibility that defects in NRG1-erbB signaling are implicated in neurodegenerative processes in the brain, similar to what we found in the periphery, needs to be examined.

References:
Chen S, Rio C, Ji RR, Dikkes P, Coggeshall RE, Woolf CJ, Corfas G. (2003) Disruption of ErbB receptor signaling in adult non-myelinating Schwann cells causes progressive sensory loss. Nat Neurosci. 6:1186-93. Epub 2003 Oct 12. Abstract

Garratt AN, Voiculescu O, Topilko P, Charnay P, Birchmeier C. (2000) A dual role of erbB2 in myelination and in expansion of the schwann cell precursor pool. J Cell Biol. 148:1035-46. Abstract

View all comments by Gabriel Corfas

Being human and the myelin on small fibers: Implications for the dementias and multiple other neuropsychiatric disorders
By examining mice, Michailov et al. (2004) might have given us an important lead about the mechanisms that make our brain (and the disorders that plague it) unique.

The human brain is unique in its high myelin content and long developmental (myelination) phase that continues until approximately the age of 50 (Bartzokis et al., 2001). Although our extensive process of myelination underlies many of our brain’s unique capabilities, it likely also underlies its unique susceptibility to highly prevalent disorders of development (autism, ADHD, schizophrenia, drug use, depression), as well as degeneration (Alzheimer’s, Parkinson’s, Lewy body and other rarer diseases) (Bartzokis, 2004a, 2004b). The large axons on which primary processes (motor and sensory) depend myelinate fully and most extensively in infancy, and are largely spared in both developmental and degenerative brain diseases despite their size and high metabolic requirements. On the other...  Read more

Being human and the myelin on small fibers: Implications for the dementias and multiple other neuropsychiatric disorders
By examining mice, Michailov et al. (2004) might have given us an important lead about the mechanisms that make our brain (and the disorders that plague it) unique.

The human brain is unique in its high myelin content and long developmental (myelination) phase that continues until approximately the age of 50 (Bartzokis et al., 2001). Although our extensive process of myelination underlies many of our brain’s unique capabilities, it likely also underlies its unique susceptibility to highly prevalent disorders of development (autism, ADHD, schizophrenia, drug use, depression), as well as degeneration (Alzheimer’s, Parkinson’s, Lewy body and other rarer diseases) (Bartzokis, 2004a, 2004b). The large axons on which primary processes (motor and sensory) depend myelinate fully and most extensively in infancy, and are largely spared in both developmental and degenerative brain diseases despite their size and high metabolic requirements. On the other hand, oligodendrocytes that differentiate later in development are increasingly complex cells that myelinate, increasing numbers of smaller caliber axons, making them more and more vulnerable. In this myelin model of human brain, these later differentiating cells represent the “Achilles’ heel” of our brain’s Internet (Bartzokis et al., 2001; Bartzokis et al., 2003).

The paper by Michailov et al. (2004) adds an essential clue to the genetic underpinnings of the differentially susceptibility of small caliber axons to both hypo- as well as hypermyelination. Although they did not specifically focus on this observation, their data showed that changing in neuregulin-1 differentially impacted myelination of smaller diameter axons. Thus, the gross function of the mice (dependent primarily on large axons) remained essentially normal. However, in the framework of the myelin model of the human brain outlined above, the differential impact of neuregulin-1 on small diameter axons takes on disproportionate significance for human neuropsychiatric diseases.

In the framework of the model, it is not surprising that defects in the region containing this gene are strongly associated with schizophrenia (Li et al., 2004; Steffanson et al., 2003), a disease whose onset is primarily in the teens and early twenties when smaller fibers are being myelinated. Patients with schizophrenia have been shown to have myelination deficits that become increasingly more pronounced as they approach middle age (Bartzokis et al., 2003; Bartzokis, 2002), and although they develop early dementia (hence, its original name of “dementia praecox”), their dementia is not of the Alzheimer’s type (reviewed in Bartzokis, 2004b). Again, in the framework of the model, the absence of severe Alzheimer’s disease lesions is not surprising since their development may require intact (“normal”) brain myelination. Thus, in older age, defects in the neuregulin genes that cause hypomyelination can be expected to be associated with non-Alzheimer’s dementias of earlier onset such as frontotemporal dementias or the risk of developing trauma-related disorders such as dementia pugilistica (reviewed in Bartzokis, 2004b), while defects in the genes that promote myelination may protect from degenerative disorders.

Neuregulin-1 and other such molecular signals represent clear targets for investigating genetic variations that may have subtle but crucial contributions to the quadratic trajectory of human brain myelin content over the lifetime. In the framework of the model, medications that impact such normal molecular mechanisms that differentially impact myelination of smaller caliber fibers could be especially useful in a wide range of human brain disorders. Influencing different disease processes with the same pharmacologic intervention may be possible by targeting different time points of increased vulnerability in the lifelong trajectory of myelin development and its subsequent degeneration (reviewed in Bartzokis, 2004b).

References:
Bartzokis G (2004a): Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer's disease. Neurobiol Aging 25:5-18. Abstract

Bartzokis G (2004b): Quadratic trajectories of brain myelin content: unifying construct for neuropsychiatric disorders. Neurobiol Aging 25:49-62.

Bartzokis G (2002): Schizophrenia: breakdown in the well-regulated lifelong process of brain development and maturation. Neuropsychopharmacology 27:672-83. Abstract

Bartzokis G, Beckson M, Lu PH, Nuechterlein KH, Edwards N, Mintz J (2001): Age-related changes in frontal and temporal lobe volumes in men: A magnetic resonance imaging study. Arch Gen Psychiatry 58:461-465. Abstract

Bartzokis G, Nuechterlein KH, Lu PH, Gitlin M, Rogers S, Mintz J (2003): Dysregulated brain development in adult men with schizophrenia: A magnetic resonance imaging study. Biol Psychiatry 53:412-421. Abstract

Li T, Stefansson H, Gudfinnsson E, Cai G, Liu X, Murray RM, Steinthorsdottir V, Januel D, Gudnadottir VG, Petursson H, Ingason A, Gulcher JR, Stefansson K, Collier DA (2004). Identification of a novel neuregulin 1 at-risk haplotype in Han schizophrenia Chinese patients, but no association with the Icelandic/Scottish risk haplotype. Mol Psychiatry. 2004 Mar 9, available online. Abstract

Stefansson H, Sarginson J, Kong A, Yates P, Steinthorsdottir V, Gudfinnsson E, Gunnarsdottir S, Walker N, Petursson H, Crombie C, Ingason A, Gulcher JR, Stefansson K, St Clair D (2003). Association of neuregulin 1 with schizophrenia confirmed in a Scottish population. Am J Hum Genet. 72(1):83-7. Abstract

View all comments by George Bartzokis