Neural and mammary gland defects in ErbB4 knockout mice genetically rescued from embryonic lethality

Abstract

Mice lacking the epidermal growth factor receptor family member ErbB4 exhibit defects in cranial neural crest cell migration but die by embryonic day 11 because of defective heart development. To examine later phenotypes, we rescued the heart defects in ErbB4 mutant mice by expressing ErbB4 under a cardiac-specific myosin promoter. Rescued ErbB4 mutant mice reach adulthood and are fertile. However, during pregnancy, mammary lobuloalveoli fail to differentiate correctly and lactation is defective. Rescued mice also display aberrant cranial nerve architecture and increased numbers of large interneurons within the cerebellum.

Besides Purkinje cells and granule neurons: an appraisal of the cell biology of the interneurons of the cerebellar cortex

“…As a consequence, these cells are capable of integrating environmental developmental signals far oV the immediate vicinity of their Wnal mitosis, in areas they reach only after protracted translocation. The observation that mice null for the ErbB4 receptor have increased numbers of large granule cell layer inhibitory interneurons suggests a role for the ErbB4/neuregulin signaling pathway in this scenario (Tidcombe et al 2003). Further, in vitro observations support the notion that such local cues include electrical activity and BDNF, which have been noted to regulate the expression of mGluR2 and parvalbumin, and also dendritic morphogenesis of cerebellar interneurons (Koscheck et al 2003;Mertz et al 2000).…”

WW domain containing E3 ubiquitin protein ligase 1 targets the full-length ErbB4 for ubiquitin-mediated degradation in breast cancer

“…One of the primary functions of ErbB4 in vivo is in the maturation of mammary glands during pregnancy and WWP1 targets ErbB4 for degradation Y Li et al lactation induction (Long et al, 2003;Tidcombe et al, 2003). ErbB4 can activate the expression of the tumor suppressor gene, BRCA1, (Muraoka-Cook et al, 2006a) and differentiation genes such as b-casein (Muraoka-Cook et al, 2008).…”

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

“…ErbB4 is essential for cardiac development. The embryonic lethality associated with constitutional disruption of ErbB4 can be bypassed by expression of a human HER4 cDNA in the heart under control of a mouse a-myosin heavy chain promoter (Tidcombe et al, 2003). ErbB4 À/À animals carrying this HER4 heart transgene reach adulthood and are fertile, but have cranial nerve and cerebellar defects, and impaired mammary differentiation and lactation.…”

“…The floxed ErbB4 and ErbB4 null mice were backcrossed into FVB background for a minimum of seven generations before breeding to generate mice for analysis. Conditional knock-out HER4 heart ErbB4 À/À mice (Tidcombe et al, 2003) were obtained from Dr Martin Gassmann. All animal experiments were performed under a Yale University Institutional Animal Care and Use Committee approved protocol.…”

“…Similarly, in mouse mammary gland development, ErbB4 signaling is important for final stages of differentiation and maintenance of lactation, but is not required for proliferation of mammary epithelial cells during puberty or in pregnancy (Jones et al, 1999;Long et al, 2003;Tidcombe et al, 2003).…”