2003 Fiscal Year Final Research Report Summary
Physiological significance of proHB-EGF ectodomain shedding in epideimal development
| Project/Area Number |
14580696
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Cell biology
|
|---|
| Research Institution | Osaka University |
|---|
Principal Investigator |
IWAMOTO Ryo Research Institute For Microbial Diseases, Department of Cell Biology, Assistant Professor, 微生物病研究所, 講師 (10213323)
|
|---|
| Project Period (FY) |
2002 – 2003
|
| Keywords | HB-EGF / ectodomain shedding / EGF family / ErbB / cardiomyopathy / valvulogenesis / epidermal remodeling / knock-in mice |
|---|
| Research Abstract |
1)HB-EGF is a member of the EGF family of giowth factors. To examine the role of HB-EGF in viva, we generated HE-EGF-knockout mice HB^<del/del>). HB^<del/del> mice developed severe heart failure with dilated ventricular chambers, similarly to conditional ErbB2 knockout mice. HB^<del/del> mice developed also enlarged cardiac valves, similarly to EGFR knockout mice. Constitulive tyrosine phosphorylation of both ErbB2 and ErbB4 was significantly reduced in HB^<del/del> hearts. These indicated that HB-EGFactivalion of ErbB is essential for normal heartfunclion.
2)HB-EGF is first synthesized as a membrane-anchored form (proHB-EGF), and its soluble form (sHB-EGF) is released by ectodomain shedding fiom proHB-EGF. To examine the significance of proHB-EGF processing in vivo, we generated mutant mice by targeted gene replacement, xpressing either an uncleavable form (HB^<uc>) or a transmembrane domain-truncated form (HB^<Δtm>) of the molecule. HB^<uc/uc> mice developed severe heart failure and e
… More
nlarged heart valves, phenotypes similar to those in proHB-EGF-null mice. On the other hand, mice canying HB^<Δtm> exhibited severe hyperplasia in both skin and heart These results indicate that ectodomain shedding of proHB-EGF is essential for HB-EGF function in viva, and that this piocess requires strict control.
3)HB^<del/del> mice did not show any abnormalities in developmental piocess of epidermis. Thus, we investigated the role of HE-EGF in re-epithelization. HB-EGF expression in adult epidermis was hardly detected at the steady state, but it was strongly induced after full-thickness wounding and topical treatment with retinoic acid (tRA). The level of hyperprolifemtion of keratinocytes induced by tRA-ireatinent and that of wound healing were estimated among the mutant mice selectively ablated HB-EGF expression in basal keratinocytes (HB^<del/del>-K5-Cre),HB^<uc/uc> mice and normal HB-EGF cDNA knock-in mice (HB^<lox/iox>) as an experimenrtal control. In HB^<del/del>-K5-Cre mice and in HBuc/uc mice, both tRA-induced epidermal hyperproliferation and wound healing activity was reduced compared with HBlox/lox mice. These indicated that the induction of HB-EGF and its ectodomain shedding is an important event in the re-epithelization in vivo. Less
|
Research Products
(8 results)
