Rab11-FIP4 is predominantly expressed in neural tissues and involved in proliferation as well as in differentiation during zebrafish retinal development.
Rab11 family interacting protein 4 (Rab11-FIP4) was initially identified in humans as an Rab11-binding protein, but its biological function has remained unknown. We cloned the zebrafish orthologue of Rab11-FIP4 (zRab11-FIP4) and analyzed its function in vivo by using antisense morpholino. zRab11-FIP4 was expressed as 2 alternative transcripts, i.e., the longer A-form predominantly expressed in neural tissues and the shorter B-form expressed ubiquitously; and in situ hybridization revealed that the A-form was the dominant form. In the developing retina, zRab11-FIP4 was expressed in progenitors throughout the retina at early stages; and then, along with the differentiation, the expression became gradually restricted to the ganglion cell layer and ciliary marginal zone. zRab11-FIP4A knockdown embryos exhibited eye phenotypes similar to those of the shh mutant, such as a small eye with impaired cell proliferation and the delay in cell-cycle exit and differentiation of retinal progenitors. The lack of induction of p57kip2 and enhanced expression of cyclin D1 were observed in the morphant retina. Importantly, the delay in cell-cycle exit was rescued by ectopic expression of either p57Kip2 or dominant-negative PKA, suggesting that Rab11-FIP4A plays pivotal roles in retinal development by regulating Shh signaling and a mechanism acting in parallel with Shh signaling in the control of cell-cycle exit.
Muto
Akihiko
A
Department of Molecular and Developmental Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan.
Arai
Ken-Ichi
K
Watanabe
Sumiko
S
D000818:Animals; D001921:Brain / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D002452:Cell Count; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D017868:Cyclic AMP-Dependent Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000096:biosynthesis / Q000235:genetics; D053823:Hedgehog Proteins; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D016376:Oligonucleotides, Antisense; D012160:Retina / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D015534:Trans-Activators / Q000502:physiology; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D020691:rab GTP-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D000099193:rab11 GTP-Binding Proteins
D002352:Carrier Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D050761:Cyclin-Dependent Kinase Inhibitor p57; D053823:Hedgehog Proteins; D009419:Nerve Tissue Proteins; D016376:Oligonucleotides, Antisense; D015534:Trans-Activators; D029961:Zebrafish Proteins; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C510147:rab11fip4a protein, zebrafish