distinct role for secreted fibroblast growth factor-binding proteins in development

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 21; pp. 8585 - 8590
• Main Authors: Gibby, Krissa A, McDonnell, Kevin, Schmidt, Marcel O, Wellstein, Anton
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 26.05.2009; National Acad Sciences
• Subjects: Animals; Avian Proteins - genetics; Avian Proteins - metabolism; Avian Proteins - secretion; Binding sites; Biological Sciences; Carrier proteins; Carrier Proteins - genetics; Carrier Proteins - metabolism; Carrier Proteins - secretion; Cell growth; Cell Line; Chick Embryo; Chickens; Developmental biology; Dual Specificity Phosphatase 1 - metabolism; Embryos; Fibroblast growth factors; Fibroblast Growth Factors - metabolism; Fibroblasts; Gene expression; Gene Expression Regulation, Developmental; Hedgehog Proteins - metabolism; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Human growth; Humans; Messenger RNA; Phenotype; Phylogeny; Poultry; Proteins; Receptors; RNA, Small Interfering - genetics; Signal Transduction; Small interfering RNA; Survival Rate
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0810952106

FGFs modulate diverse biological processes including embryonic development. Secreted FGF-binding proteins (BPs) can release FGFs from their local extracellular matrix storage, chaperone them to their cognate receptors, and thus modulate FGF signaling. Here we describe 2 chicken BP homologs (chBP) that show distinct expression peaks at embryonic days E7.5 (chBP2) and E11.5 (chBP1), although their tissue distribution is similar (skin = intestine>lung>heart, liver). Embryos were grown ex ovo to monitor the phenotypic impact of a timed in vivo knockdown of expression peaks by microinjection of specific siRNAs targeted to either of the chBPs. Knockdown of peak expression of chBP2 caused embryonic lethality within <5 days. Surviving embryos showed defective ventral wall closure indicative of altered dorsoventral patterning. This defect coincided with reduced expression of HoxB7 but not HoxB8 that are involved in the control of thoracic/abdominal segment morphology. Also, MAPK phosphatase 3, a negative regulator of FGF signaling, and sonic hedgehog that can participate in feedback control of the FGF pathway were reduced, reflecting altered FGF signaling. Knockdown of the chBP1 expression peak caused embryonic lethality within <3 days although no distinct morphologic phenotype or pathways alterations were apparent. We conclude that BPs play a significant role in fine-tuning the complex FGF signaling network during distinct phases of embryonic development.