Physiological function of HB-EGF : Study of the knock-in mice of the mutant form of HB-EGF

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The EOF family of growth factors is released from the cell surface by proteolytic processing of the membrane-anchored precursors, dubbed ectodomain shedding ; the biological significance of ectodomain shedding in vivo, however, remains unknown. Heparin-binding EGF-like growth factor (HB-EGF) is also derived from a membrane-anchored precursor (proHB-EGF).We demonstrate that the control of ectodomain shedding of proHB-EGF is a process essential for normal mouse development. In the transfection experiments of SHB-EGF and proHB-EGF into mouse embryonic skins, exogenous overexpression of SHB-EGF resulted in embryonic epidermal hyperplasia, while proHB-EGF expression did not cause any abnormalities in embryonic epidermis. These suggest that even following overexpression, proHB-EGF ectodomain shedding is strictly controlled in the embryonic epidermis.Next we prepared mice carrying a gene encoding transmembrane-domain-truncated proHB-EGF (HB4^ATM) by targeted gene replacement. These mice produce a soluble form offtB-EGF (SHB-EGF), instead ofproHB-EGF. Chimeric mice carrying HB^ATM and their Fl heterozygotes exhibit severe skin hyperplasia with accelerated proliferation and perturbed differentiation of keratinocytes. We also observed ventricular well hyperplasia in the heart, with most of the animals dying in either the embryonic or neonatal stages. These indicate that the proteolytic processing of proHB-EGF ectodomain is strictly controlled in vivo. Our results also indicate that ectodomain shedding is a vital post-translational control of growth factor activity.