title: Midkine-A functions upstream of Id2a to regulate cell cycle kinetics in the developing vertebrate retina.
abstract: BACKGROUND
  Midkine is a small heparin binding growth factor expressed in numerous tissues during development. The unique midkine gene in mammals has two paralogs in zebrafish: midkine-a (mdka) and midkine-b (mdkb). In the zebrafish retina, during both larval development and adult photoreceptor regeneration, mdka is expressed in retinal stem and progenitor cells and functions as a molecular component of the retina's stem cell niche. In this study, loss-of-function and conditional overexpression were used to investigate the function of Mdka in the retina of the embryonic zebrafish.
  
  
  RESULTS
  The results show that during early retinal development Mdka functions to regulate cell cycle kinetics. Following targeted knockdown of Mdka synthesis, retinal progenitors cycle more slowly, and this results in microphthalmia, a diminished rate of cell cycle exit and a temporal delay of cell cycle exit and neuronal differentiation. In contrast, Mdka overexpression results in acceleration of the cell cycle and retinal overgrowth. Mdka gain-of-function, however, does not temporally advance cell cycle exit. Experiments to identify a potential Mdka signaling pathway show that Mdka functions upstream of the HLH regulatory protein, Id2a. Gene expression analysis shows Mdka regulates id2a expression, and co-injection of Mdka morpholinos and id2a mRNA rescues the Mdka loss-of-function phenotype.
  
  
  CONCLUSIONS
  These data show that in zebrafish, Mdka resides in a shared Id2a pathway to regulate cell cycle kinetics in retinal progenitors. This is the first study to demonstrate the function of Midkine during retinal development and adds Midkine to the list of growth factors that transcriptionally regulate Id proteins.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan, W, K, Kellogg Eye Center, 1000 Wall Street, Ann Arbor, MI 48105-0714, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Luo
authors.forename: Rosa A
authors.initials: RA
authors.lastname: Uribe
authors.forename: Sarah
authors.initials: S
authors.lastname: Hayton
authors.forename: Anda-Alexandra
authors.initials: AA
authors.lastname: Calinescu
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Gross
authors.forename: Peter F
authors.initials: PF
authors.lastname: Hitchcock
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001973:Bromodeoxyuridine / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004625:Embryo, Nonmammalian; D005434:Flow Cytometry; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D051797:Inhibitor of Differentiation Protein 2 / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D007814:Larva; D000078792:Midkine; D060172:Morpholinos / Q000494:pharmacology; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012160:Retina / Q000166:cytology* / Q000196:embryology / Q000254:growth & development; D055153:Stem Cell Niche / Q000187:drug effects / Q000235:genetics*; D015027:Zebrafish / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; D006657:Histones; C577676:Id2a protein, zebrafish; D051797:Inhibitor of Differentiation Protein 2; D060172:Morpholinos; D012333:RNA, Messenger; D029961:Zebrafish Proteins; D000078792:Midkine; D001973:Bromodeoxyuridine