10 October 2006. Neuregulin and its ErbB4 receptor team up to silence genes and thereby determine whether neural precursor cells will wind up as neurons or astrocytes, according to a paper published October 6 in Cell, by Gabriel Corfas and colleagues at Harvard Medical School in Boston.
The Corfas group reports that following neuregulin binding to ErbB4, the activated receptor is cleaved, liberating the intracellular cytoplasmic domain. This domain translocates to the nucleus and represses the expression of astrocytic genes, thereby steering the cells toward a neuronal fate. Using ErbB4 knockout mice, the researchers further found that neuregulin signaling accounts for the classic delay in astrogenesis during development.
Squelching gene expression
A bonus of linking the neuregulin-1 gene to schizophrenia (Stefansson et al., 2002) was that it came with a history, including an emerging role in neurodevelopment, not to mention binding partners to investigate (see SRF related news story). One of these, the ErbB4 receptor, has drawn a great deal of attention recently in schizophrenia circles, both in terms of genetics and neurodevelopment (see SRF related news story) and in molecular biology (see SRF related news story).
ErbB4 is a member of the EGF receptor tyrosine kinase family, known for years to signal via a kinase cascade activated by ligand binding. More recently, another potential signaling mechanism was discovered, in which the receptor is proteolytically cleaved by the γ-secretase complex, liberating the intracellular cytoplasmic domain (E4ICD) that undergoes nuclear translocation (see Alheimer Research Forum related news story and Lee et al., 2002). The γ-secretase is a longtime holy grail of the Alzheimer research community because it cleaves the amyloid precursor protein (APP), releasing the toxic β-amyloid peptide found in amyloid plaques. Recently, the γ-secretase has been identified as presenilin, in complex with several other proteins (for plenty more reading on this issue, visit the Alzheimer Research Forum). The γ-secretase processing of ErbB4 resembled that of APP or the important developmental regulator Notch, right down to the intracellular release of the cytosolic domain and its subsequent association with transcriptional regulatory proteins in the nucleus. Not all Erb4 isoforms undergo such processing, however. It only occurs with ErbB4, and then only with one splice variant that is highly expressed in brain. This pattern suggested a role in the brain for the E4ICD, but just what it did was unclear.
First author S. Pablo Sardi and colleagues addressed that mystery by showing that upon neuregulin binding, the active ErbB4 receptor forms a complex with the signaling adaptor protein TAB2. Upon receptor cleavage, the E4ICD-TAB2 complex rapidly moves from the cytosol to the nucleus, where it joins up with the transcriptional co-repressor N-CoR.
The authors found a physiological role for ErbB4 cleavage in neural precursor cells from rats. No matter what they threw at the cells—γ-secretase inhibitors, RNAi to various pathway components, or kinase-dead or non-cleavable variants of ErbB4—the results were consistent: neuregulin binding stimulated presenilin-dependent cleavage of ErB4, and the released E4ICD complexed with TAB2 and N-CoR to shut down astrocytic gene expression and differentiation. In vivo studies with ErbB4 knockout mice backed up this idea, and showed that E4ICD was necessary and sufficient to regulate astrogenesis in the intact developing cortex. Of note, ErbB4 signaling also plays a role in dendrite morphology, neurotransmitter receptor expression, and neuronal survival.
In regard to schizophrenia, Corfas suggests that perturbations along this pathway might lead to the premature formation of astrocytes. “Changes in the timing in which different neural cells are produced could lead to alterations in brain wiring,” he said in a press release issued by Children's Hospital Boston. “This would lead to alterations in cognitive function such as those seen in schizophrenia—which is now considered to be a developmental disorder—and potentially in other diseases such as autism.”
An accompanying commentary by Joseph Schlessinger, Yale University, New Haven, Connecticut, and Mark Lemmon, University of Pennsylvania, Philadelphia, brings up yet another interesting aspect of the story: the elucidation of a new and potentially more general signaling mechanism for receptor tyrosine kinases. With the demonstration of the dual-protease signaling pathway, they write, “the work sets a standard with which to challenge all other studies of direct nuclear signaling by RTKs.”—Pat McCaffrey and Hakon Heimer.
Sardi PS, Murtie J, Koirala S, Patten BA, Corfas G. Presenilin-dependent ErbB4 nuclear signaling regulates the timing of astrogenesis in the developing brain. Cell. 2006 Oct 6; 127:185-197. Abstract
Schlessinger J, Lemmon MA. Nuclear signaling by receptor tyrosine kinases: The first robin of spring. Cell. 2006 Oct 6; 127:45-48. Abstract