Neuregulins are members of the epidermal growth factor family of related ligands that exert pleotropic effects during development on the Schwann cell lineage. The receptor complex activated by neuregulin in Schwann cells consists of HER2 (erbB2) and HER3 (erbB3). The intracellular signaling events that follow activation of the HER2/HER3 receptor complex in primary cells, and in particular in Schwann cells, are poorly understood. We have found that neuregulin induces the rapid association of the guanine nucleotide exchange factor SOS with the HER2/HER3 receptor complex. The association of SOS with the HER2/HER3 receptor complex is preceded by the rapid association of Grb2 with the HER2/HER3 receptor complex. Far Western analysis indicates that Grb2 and SOS bind exclusively to HER2 in the HER2/HER3 receptor complex.
"the possibility that a peripheral target tissue disturbance rather than a primary neuron dysfunction may account for the failure of Pacinian corpuscles to form in Er81 null mice. Interactions between afferent neurons and Schwann cells, which form the inner core of Pacinian corpuscles, involve multiple reciprocal and/or bidirectional signaling systems comprising neuregulins and ErbB receptors and acting in both a paracrine and juxtacrine manner (Meintanis et al., 2001; Goodearl et al., 2001; Lyons et al., 2005). ETS factors are involved in neuregulin/ErbB signaling between afferent neurons and their target Schwann cells and mesenchymal cells, which form the inner and outer capsules of the corpuscles (Parkinson et al., 2002; Falls, 2003). "
[Show abstract][Hide abstract] ABSTRACT: ER81, a member of the ETS family of transcription factors, is involved in processes of specification of neuronal identity, control of sensory-motor connectivity, and differentiation of muscle spindles. Spindles either degenerate or are abnormal in mutant mice lacking ER81. We examined whether ER81 is required for the development of another class of mechanoreceptors, the Pacinian corpuscle. ER81 was expressed by the inner core cells of the corpuscles, as reflected by expression of the lacZ reporter gene in Er81(+/lacZ) mutants, thereby suggesting a role for ER81 in the corpuscle development. No Pacinian corpuscles or their afferent nerve fibers were present in the crus of Er81 null mice at birth. Legs of mutant embryos examined at E16.5 were also devoid of the corpuscles, but not of their afferents. Thus, Pacinian corpuscles do not form, and their afferents do not survive, in the absence of ER81. A deficiency of dorsal root ganglia neurons expressing calretinin, a marker for neurons subserving Pacinian corpuscles, correlated with the absence of corpuscles and their afferents in Er81 null mice. These observations indicate a requirement for ER81 in the assembly of Pacinian corpuscles and the survival of the sensory neurons that innervate them.
[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease (AD) is a progressive senile dementia characterized by deposition of a 4 kDa peptide of 39-42 residues known as amyloid beta-peptide (Abeta) in the form of senile plaques and the microtubule associated protein tau as paired helical filaments. Genetic studies have identified mutations in the Abeta precursor protein (APP) as the key triggers for the pathogenesis of AD. Other genes such as presenilins 1 and 2 (PS1/2) and apolipoprotein E (APOE) also play a critical role in increased Abeta deposition. Several biochemical and molecular studies using transfected cells and transgenic animals point to mechanisms by which Abeta is generated and aggregated to trigger the neurodegeneration that may cause AD. Three important enzymes collectively known as "secretases" participate in APP processing. An enzymatic activity, beta-secretase, cleaves APP on the amino side of Abeta producing a large secreted derivative, sAPPbeta, and an Abeta-bearing membrane-associated C-terminal derivative, CTFbeta, which is subsequently cleaved by the second activity, gamma-secretase, to release Abeta. Alternatively, a third activity, alpha-secretase, cleaves APP within Abeta to the secreted derivative sAPPalpha and membrane-associated CTFalpha. The predominant secreted APP derivative is sAPPalpha in most cell-types. Most of the secreted Abeta is 40 residues long (Abeta40) although a small percentage is 42 residues in length (Abeta42). However, the longer Abeta42 aggregates more readily and was therefore considered to be the pathologically important form. Advances in our understanding of APP processing, trafficking, and turnover will pave the way for better drug discovery for the eventual treatment of AD. In addition, APP gene regulation and its interaction with other proteins may provide useful drug targets for AD. The emerging knowledge related to the normal function of APP will help in determining whether or not the AD associated changes in APP metabolism affect its function. The present review summarizes our current understanding of APP metabolism and function and their relationship to other proteins involved in AD.
NeuroMolecular Medicine 02/2002; 1(1):1-31. DOI:10.1385/NMM:1:1:1 · 3.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Neuregulins (NRG) play important roles in the development, maintenance, and repair of the nervous system, with influences on neuronal migration, synaptogenesis, receptor subunit composition, and the proliferation/survival of oligodendrocytes and Schwann cells. However, the precise detail of how the NRGs signal through ErbB receptors, particularly at central synapses, is incomplete. The receptor kinase domain provides sites for association with adaptor proteins. In addition, evidence from recent reports suggests that ErbB2/4 receptors, through their C-terminal amino acids, can form specific associations with scaffolding proteins. The existence of such assemblies expands the range of signaling cascades available to the NRGs.
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