27 Mar 2003

The family of neuregulin-1 growth and differentiation factors is rapidly piquing the interest of researchers in areas ranging from schizophrenia to Alzheimer's disease. In the March 20 early online PNAS, Eva Anton, Ralf Schmid, and their colleagues at the University of North Carolina, Chapel Hill; Yale University in New Haven, Connecticut; and CeNes Pharmaceuticals in Norwood, Massachusetts, report that neuregulin-1 signaling involving the erbB2 receptor pathway-possibly in concert with Notch signaling-is critical for cellular differentiation that allows appropriate cortical development. This finding has no direct implications for the above diseases, but hints at possible connections to be explored.

The distinctive laminar structure of the mammalian neocortex is constructed in large part thanks to a scaffolding of radial glial cells that forms during development. As shown in pioneering work by Pasko Rakic of Yale and others, these cells are multi-talented: Their long fibers extending from the unfolding brain’s ventricles to its surface provide migrational paths and cues for newly born neurons to follow from germinal zones to their final destinations. Moreover, researchers including Gotz, Miyata, and Kriegstein have shown that radial glial cells are themselves progenitor cells. They can give rise to neurons and convert to astrocytes after embryogenesis, when a guiding scaffold is no longer needed.

One of the molecules expressed by both neurons and glial precursors in this developmental environment is neuregulin-1 (NRG-1), which affects cellular differentiation via the protein tyrosine kinase receptors erbB2, -B3, and -B4. Anton and coworkers sought to determine whether, and by what pathways, NRG-1 affects the development and differentiation of radial glial cells. Continuing earlier work, they found that the absence of NRG-1 in knockout mice reduced the number of radial glia generated by cultured embryonic neuroepithelial cells. The addition of exogenous NRG-1 to these cultures restored the production of radial glia.

Anton and colleagues also found evidence suggesting that NRG-1 is crucial not just for the development of radial glial cells, but also for the maintenance of the scaffold, and that the erbB2 receptor modulates this. In vitro, blocking erbB2 activity prevented the radial glia from assuming their characteristic shape; in vivo, interfering with erbB2 produced aberrant radial glial development, including their premature transformation into astrocytes.

Further experiments indicated that erbB2 mediates a dynamic balance between radial glial cells and astrocytes. For example, when erbB2 is reexpressed in mature astrocytes, the ratio of radial glia to astrocytes increases, indicating that NRG-1 signaling via erbB2 induced astrocytes to become radial glia.

The authors suggest that there might be reason to investigate the potential of the NRG-1-erbB2 pathway to induce neurogenesis in the adult brain. "Functional induction of erbB2 in mature astrocytes may facilitate their ability to support cell migration or neurogenesis during ongoing maintenance of neural circuitry in mature CNS," they write.

Of particular interest to Alzheimer’s researchers may be recent evidence that Notch signaling is critical for the development of radial glial cells. Notch and amyloid precursor protein are structurally similar and are both cleaved by γ-secretase to produce similar transcriptionally active intracellular domains (see ARF related news story). Other research indicated that γ-secretase cleaves erbB4 (see ARF related news story).

Earlier this year, researchers reported that NRG-1 and the erbB family of receptors continue to be expressed in aging human brain, but that the distribution of expression changes in AD and that erbB4 and NRG-1 are associated with neuritic plaques (Chaudhury et al. 2003). In mice doubly transgenic for AßPP and presenilin-1 mutations, both erbB2 and -B4, along with NRG-1, were associated with neuritic plaques. In their current paper, Anton and his colleagues found evidence that Notch signaling affects radial glial cell development by upregulating the expression of erbB2 and thereby increasing the response of radial glial cells to NRG signals. Neuregulin also recently emerged as a possible genetic risk factor for schizophrenia, a disease that is clearly distinct from AD, but shows some overlap in that AD patients can develop psychotic symptoms in later stages of the disease (Stefansson et al, 2002; Stefansson et al, 2003).—Hakon Heimer

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References

News Citations

1. More Clues in the Case, but γ-Secretase Remains at Large 22 Nov 2002
2. γ-Secretase Found to Cleave Receptor Tyrosine Kinase ErbB-4 22 Nov 2002

Paper Citations

1. Chaudhury AR, Gerecke KM, Wyss JM, Morgan DG, Gordon MN, Carroll SL. Neuregulin-1 and erbB4 immunoreactivity is associated with neuritic plaques in Alzheimer disease brain and in a transgenic model of Alzheimer disease. J Neuropathol Exp Neurol. 2003 Jan;62(1):42-54. PubMed.
2. Hicks AA, Pétursson H, Jónsson T, Stefánsson H, Jóhannsdóttir HS, Sainz J, Frigge ML, Kong A, Gulcher JR, Stefánsson K, Sveinbjörnsdóttir S. A susceptibility gene for late-onset idiopathic Parkinson's disease. Ann Neurol. 2002 Nov;52(5):549-55. PubMed.
3. Modin H, Masterman T, Thorlacius T, Stefánsson M, Jónasdóttir A, Stefánsson K, Hillert J, Gulcher J. Genome-wide linkage screen of a consanguineous multiple sclerosis kinship. Mult Scler. 2003 Mar;9(2):128-34. PubMed.

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