The ErbB4 Neuregulin Receptor Mediates Suppression of Oligodendrocyte Maturation

Abstract

Neuregulin is required for proper oligodendrocyte development, but which receptors are involved and whether neuregulin promotes or inhibits maturation remain controversial. To assess the roles of the neuregulin receptor ErbB4 in oligodendrocyte development, we examined oligodendrocyte initiation and maturation in cultures derived from erbB4 knock-out mice and rat spinal cord in the presence of neutralizing erbB4 antibodies. No differences in the development of O4 ϩ oligodendrocytes were detected in the presence or absence of erbB4 signaling. All four epidermal growth factor receptor family members were detected in the ventral neural tube at approximately the time of initial oligodendrocyte development, consistent with redundancy in neuregulin receptor signaling at the onset of oligodendrocyte development. In contrast, greater numbers of differentiated (monoclonal antibody O1 ϩ ) oligodendrocytes developed in neural tube explants from erbB4 ؊/؊ mice than either erbB4 ؉/؉ or erbB4 ؉/؊ littermates as well as in cultures treated with anti-erbB4. These data indicate that ErbB4 is not required for oligodendrocyte development and, in fact, inhibits oligodendrocyte lineage maturation. Together with previous studies, these data suggest a model in which early oligodendrocyte lineage development is regulated by promiscuous neuregulin receptor signaling, but subsequent lineage progression occurs through a balance of receptor-specific promotion or inhibition of maturation.

Sensory afferents regenerated into dorsal columns after spinal cord injury remain in a chronic pathophysiological state

“…One possibility is that the dense extracellular matrix that forms at injury sites limits oligodendrocyte differentiation. A high concentration of neuregulin within the matrix, for example, might prevent the differentiation of OPCs into myelinating oligodendrocytes (Canoll et al 1996;Sussman et al 2005). In this regard, laminin and other integrin ligands within the matrix could also alter the development of myelinating cells (Colognato et al 2002).…”

The epidermal growth factor receptor family: Biology driving targeted therapeutics

“…Reduced ductal elongation and branching [193] erbB3 [129,194,195] Cardiac defect rescue Failure of mammary gland lobuloalveolar development, impaired lactation Cranial nerve defects Increased cerebellar large interneurons [196] Ventricular cardiomyocyte-specific deletion Dilated cardiomyopathy [130] Cell Mol Life Sci. Author manuscript; available in PMC 2011 March 17.…”

Directing traffic in neural cells: determinants of receptor tyrosine kinase localization and cellular responses

“…OL maturation, myelin formation, dopaminergic function (Sussman et al 2005;Roy et al 2007); Neural crest and neuroblast migration, differentiation of olfactory interneurons (Tidcombe et al 2003;Anton et al 2004); Glutamatergic synapse function (Li et al 2007); Repression of astrogenesis (Sardi et al 2006) EGFR (ErbB1) Survival of neurons in the frontal cortex, olfactory bulb, and thalamus. Survival and proliferation of cortical astrocytes (Sibilia et al 1998;Wagner et al 2006); Astrocyte development and neuronal survival (Kornblum et al 1998 Regulation of neural tube development (Deng et al 1997;Hasegawa et al 2004); OL differentiation (Zhou et al 2006) p75NTR Negative regulation of hippocampal pyramidal neuron dendritic morphology and neurite outgrowth (Zagrebelsky et al 2005); Schwann cell migration, remyelination (Bentley and Lee 2000;Song et al 2006;Tomita et al 2007) TrkA Development of sensory sympathetic and cholinergic neurons Fagan et al 1996) TrkB Development of motor and/or sensory neurons (Ernfors et al 1994;Klein 1994;Pinon et al 1996); Interneuron migration (Polleux et al 2002) TrkC Development of sensory neurons Liebl et al 1997) 1998; Hirota et al 2004), in which cytoplasmic domains of the receptor are no longer accessible to signaling proteins, rendering the receptor signaling incompetent.…”