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Teratogenic effects of retinoic acid are modulated in mice lacking expression of epidermal growth factor and transforming growth factor‐α

Teratogenic effects of retinoic acid are modulated in mice lacking expression of epidermal growth... BACKGROUND Epidermal growth factor (EGF) and transforming growth factor‐α (TGFα) regulate cell proliferation and differentiation in the embryo. The induction of cleft palate (CP) by all trans‐retinoic acid (RA) was associated with altered expression of TGFα, EGF receptor, and binding of EGF. This study uses knockout (KO) mice to examine the roles of EGF and TGFα in teratogenic responses of embryos exposed to RA. METHODS Pregnant wild‐type (WT) mice of mixed genetic background, EGF KO, C57BL/6J, and TGFα KO mice were given a single oral dose of RA (100 mg/kg, 10 ml/kg) or corn oil on GD 10 at 12 PM, GD 11 at 12 PM or 4 PM, or GD 12 at 8 AM or 12 PM (plug day = GD 0). GD 18 fetuses were examined for external, visceral, and skeletal effects. RESULTS After exposure to RA on GD 12, the incidence of CP in EGF KO was significantly reduced relative to WT. In TGFα KO fetuses, RA exposure on GD 10 increased the incidence of CP versus C57BL/6J. The incidence of skeletal defects in the limbs, vertebrae, sternebrae, and ribs were also affected by lack of expression of EGF or TGFα with region‐specific amelioration or exacerbation of the effects of RA. In TGFα KO fetuses, incidences of forelimb long bone and digit defects increased relative to C57BL/6J. In EGF KO fetuses, relative to WT, the incidence of hindlimb oligodactyly was increased. In EGF KO, but not WT, RA produced short, bent radius, humerus, and ulna. Both TGFα and EGF KO mice had increased incidences of dilation of the renal pelvis and this was reduced by RA. CONCLUSIONS RA exposure produced skeletal and visceral defects in all genotypes; however, EGF or TGFα KO influenced the incidence and severity of defects. This study supports a role for EGF and TGFα in the response to RA. Birth Defects Research (Part A), 2005. Published 2005 Wiley‐Liss, Inc. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Birth Defects Research Part A Wiley

Teratogenic effects of retinoic acid are modulated in mice lacking expression of epidermal growth factor and transforming growth factor‐α

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References (55)

Publisher
Wiley
Copyright
Copyright © 2005 Wiley‐Liss, Inc., A Wiley Company
ISSN
1542-0752
eISSN
1542-0760
DOI
10.1002/bdra.20117
pmid
15799028
Publisher site
See Article on Publisher Site

Abstract

BACKGROUND Epidermal growth factor (EGF) and transforming growth factor‐α (TGFα) regulate cell proliferation and differentiation in the embryo. The induction of cleft palate (CP) by all trans‐retinoic acid (RA) was associated with altered expression of TGFα, EGF receptor, and binding of EGF. This study uses knockout (KO) mice to examine the roles of EGF and TGFα in teratogenic responses of embryos exposed to RA. METHODS Pregnant wild‐type (WT) mice of mixed genetic background, EGF KO, C57BL/6J, and TGFα KO mice were given a single oral dose of RA (100 mg/kg, 10 ml/kg) or corn oil on GD 10 at 12 PM, GD 11 at 12 PM or 4 PM, or GD 12 at 8 AM or 12 PM (plug day = GD 0). GD 18 fetuses were examined for external, visceral, and skeletal effects. RESULTS After exposure to RA on GD 12, the incidence of CP in EGF KO was significantly reduced relative to WT. In TGFα KO fetuses, RA exposure on GD 10 increased the incidence of CP versus C57BL/6J. The incidence of skeletal defects in the limbs, vertebrae, sternebrae, and ribs were also affected by lack of expression of EGF or TGFα with region‐specific amelioration or exacerbation of the effects of RA. In TGFα KO fetuses, incidences of forelimb long bone and digit defects increased relative to C57BL/6J. In EGF KO fetuses, relative to WT, the incidence of hindlimb oligodactyly was increased. In EGF KO, but not WT, RA produced short, bent radius, humerus, and ulna. Both TGFα and EGF KO mice had increased incidences of dilation of the renal pelvis and this was reduced by RA. CONCLUSIONS RA exposure produced skeletal and visceral defects in all genotypes; however, EGF or TGFα KO influenced the incidence and severity of defects. This study supports a role for EGF and TGFα in the response to RA. Birth Defects Research (Part A), 2005. Published 2005 Wiley‐Liss, Inc.

Journal

Birth Defects Research Part A – Wiley

Published: Apr 1, 2005

Keywords: EGF; TGF; retinoic acid; cleft palate; limb defects

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