Studies on epidermal growth factor receptor signaling in vertebrate limb patterning.
The epidermal growth factor receptor (EGFR) regulates multiple patterning events in Drosophila limb development, but its role in vertebrate limb morphogenesis has received little attention. The EGFR and several of its ligands are expressed in developing vertebrate limbs in manners consistent with potential patterning roles. To gain insight into functions of EGFR signaling in vertebrate limb development, we expressed a constitutively active EGFR in developing chick limbs in ovo. Expression of activated EGFR causes pre- and postaxial polydactyly, including mirror-image-type digit duplication, likely due to induction of ectopic expression and/or modulation of genes involved in anterior-posterior (AP) patterning such as Sonic hedgehog (Shh), dHand, Patched (Ptc), Gli3, Hoxd13, Hoxd11, bone morphogenetic protein 2 (Bmp2), Gremlin, and FGF4. Activation of EGFR signaling dorsalizes the limb and alters expression of the dorsal-ventral (DV) patterning genes Wnt7a, Lmx, and En1. Ectopic and/or extended FGF8 expressing apical ectodermal ridges (AERs) are also seen. Interdigital regression is inhibited and the digits fail to separate, leading to syndactyly, likely due to antiapoptotic and pro-proliferative effects of activated EGFR signaling on limb mesoderm, and/or attenuation of interdigital Bmp4 expression. These findings suggest potential roles for EGFR signaling in AP and DV patterning, AER formation, and cell survival during limb morphogenesis.
Omi
Minoru
M
Center for Limb and Skeletal Development, Department of BioStructure and Function, School of Dental Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
Fisher
Melanie
M
Maihle
Nita J
NJ
Dealy
Caroline N
CN
D000818:Animals; D000880:Anthraquinones / Q000378:metabolism; D019521:Body Patterning / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D016923:Cell Death; D002642:Chick Embryo; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005121:Extremities / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental; D017689:Polydactyly / Q000235:genetics; D012190:Retroviridae / Q000235:genetics / Q000502:physiology; D012192:Retroviridae Infections / Q000196:embryology / Q000235:genetics / Q000821:virology; D015398:Signal Transduction; D013576:Syndactyly / Q000235:genetics
D000880:Anthraquinones; D019485:Bone Morphogenetic Proteins; C016336:dactylariol; D066246:ErbB Receptors