Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor

Abstract

Various in vitro studies have suggested that ErbB4 (HER4) is a receptor for the neuregulins, a family of closely related proteins implicated as regulators of neural and muscle development, and of the differentiation and oncogenic transformation of mammary epithelia. Here we demonstrate that ErbB4 is an essential in vivo regulator of both cardiac muscle differentiation and axon guidance in the central nervous system (CNS). Mice lacking ErbB4 die during mid-embryogenesis from the aborted development of myocardial trabeculae in the heart ventricle. They also display striking alterations in innervation of the hindbrain in the CNS that are consistent with the restricted expression of the ErbB4 gene in rhombomeres 3 and 5. Similarities in the cardiac phenotype of ErbB4 and neuregulin gene mutants suggest that ErbB4 functions as a neuregulin receptor in the heart; however, differences in the hindbrain phenotypes of these mutants are consistent with the action of a new ErbB4 ligand in the CNS.

Differential expression of NDF/neuregulin receptors ErbB-3 and ErbB-4 and involvement in inhibition of neuronal differentiation

“…It has been previously shown by using Northern blot analysis, that the two NDF receptors are widely expressed in various epithelial cell lines (Prigent et al, 1992;Plowman et al, 1993). In addition, in situ hybridization detected erbB-3 transcripts in Schwann cell precursors and in cranial ganglia cells , whereas erbB-4 transcripts were detected in the heart, brain and embryonic hindbrain (Lai and Lemke, 1991;Gassmann et al, 1995).…”

“…ErbB-2, the most oncogenic member of the family, has no known ligand, but by decelerating ligand dissociation, it functions as a shared signaling subunit of all direct receptors (Graus-Porta et al, 1995;Karunagaran et al, 1996). Gene targeting experiments supported this notion and added more functions to the list of neuregulin roles: ErbB-2-de®cient mice (Lee et al, 1995) shared a similar phenotype with both NDF/ neuregulin-knockout animals Kramer et al, 1996), and with ErbB-4-defective mice (Gassmann et al, 1995), in that formation of the heart trabeculae was impaired, causing embryonic lethality. In addition, NDF-and ErbB-2-de®cient mice showed similar alterations in the developing nervous system; the cranial ganglia did not develop normally.…”

“…In addition, NDF-and ErbB-2-de®cient mice showed similar alterations in the developing nervous system; the cranial ganglia did not develop normally. In addition, NDF mutants lacked Schwann cell precursors along peripheral projections from the spinal cord , and ErbB-4-de®cient mice displayed no loss of cells of the cranial sensory ganglia, but existing axons miss-innervated the hind brain (Gassmann et al, 1995).…”

Formation of Neu/ErbB2-induced mammary tumors is unaffected by loss of ErbB4

“…Mice homozygous for the loxP-flanked ErbB4 allele appear normal and are fertile. Cre-mediated recombination of the loxP flanked ErbB4 allele (flox) will excise the second exon, which results in the same loss-of-function mutation as reported for the null allele (Gassmann et al, 1995). To specifically delete ErbB4 in the mammary epithelium, Cre recombinase expression was driven by the MMTV promoter.…”

“…ErbB4 null mice (Gassmann et al, 1995) were obtained from Dr Martin Gassmann. MMTV-Neu mice (Guy et al, 1992) were obtained from Jackson Laboratories (strain name: FVB/N-TgN(MMTVneu) 202Mul/J, Stock number: 002376), and MMTV-Cre mice (Andrechek et al, 2000) were obtained from Dr William Muller, McGill University.…”