Tidcombe, Hester Gabrielle Anne; (2003) Investigations into the role of ErbB4 in mouse development. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

ErbB4 is the fourth and, to date, final member of the ErbB family of receptor tyrosine kinases, which includes the EGF receptor. ErbB receptors are expressed in many tissues during development, and thought to have roles in proliferation, survival, and differentiation. Additionally, their expression is deregulated in many tumour types. Mice have previously been created which lack the ErbB4 receptor. These show defects in cranial neural crest cell migration and axon pathfinding, but die by embryonic day (E) 10.5 due to failure of trabeculation to occur in the heart. To circumvent this mid-embryonic lethality and to allow the study of later genotypes, I have rescued the cardiac defect in ErbB4-/- mice using a construct expressing human ErbB4 (HER4) under a cardiac-specific promoter. Expression of this construct is shown to be specific to the heart. ErbB4-/- HER4heart mice survive to adulthood and appear superficially normal. However, fewer ErbB4-/- rescued pups are born than predicted by Mendelian genetics. Additionally, ErbB4-/- HER4heart mothers fail to rear most of their pups, probably due to a lactation defect. I demonstrate that ErbB4-/- HER4heart breast fails to differentiate correctly during pregnancy, and also that ErbB4 regulates phosphorylation of Stat5, a central molecule in milk production. The ErbB4-/- neural crest and cranial nerve phenotype is shown to be replicated by ErbB4-/- HER4heart embryos, and an aberrant nerve linking the trigeminal and facial ganglia persists at E17.5. I also show results of a separate study into the roles of sulphated proteoglycans in wild type and ErbB4-/- embryonic hindbrain regions.

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