title: Pituitary Adenylate Cyclase-Activating Peptide (PACAP), a Novel Secretagogue, Regulates Secreted Morphogens in Newborn Rat Retina.
abstract: Pituitary adenylate cyclase-activating peptide (PACAP)1-38 has been reported to be responsible for regulation of a disparate array of developmental processes in the central nervous system, and its antiapoptotic effect has been revealed in numerous models, pointing to its relevance in the etiology of neurodegenerative disorders. However, its function in retinal development remains unclear. Here, we aimed to point out that versatility can be achieved through interaction with other regulators, in which PACAP can act indirectly on the retinal microenvironment.
  
  
  
  Wistar rats at age postnatal day 1 were injected intravitreally with PACAP or PAC1 receptor antagonist (PACAP6-38, M65) or VPAC1 antagonist (PG97-269) alone or in combination. Retinas were removed at 3, 6, 12, or 24 hours after injection. Changes in mRNA level were assessed using quantitative PCR, whereas changes in protein levels were measured by Western blot.
  
  
  
  Intravitreal injection of PACAP or PAC1 receptor antagonists or the VPAC1 antagonist showed that PACAP receptors regulate the expression of five key secreted molecules (i.e., Fgf1, Bmp4, Wnt1, Gdf3, and Ihh), wherease other crucial morphogens (i.e., Fgf2, Fgf4, Fgf8, Fgf9, Shh, and Bmp9) were not affected. Pharmacologic dissection revealed that both PAC1 and VPAC1 induced downstream signaling and could cause upregulation of Fgf1, Bmp4, and Wnt1, whereas expression of Gdf3 might be mediated through the VPAC2 receptor.
  
  
  
  Our data are the first to shed light on PACAP as a secretagogue regulating a sustained production of morphogens, which in turn could enable PACAP to serve as a mitogen for retinal cells, to induce ganglion cell differentiation, and to contribute to RPE development.
authors.affiliation: Department of Ophthalmology and Visual Sciences, School of Medicine, University of Utah, Salt Lake City, Utah, United States.
authors.forename: Monika
authors.initials: M
authors.lastname: Lakk
authors.affiliation: Department of Experimental Zoology and Neurobiology, University of Pécs, Pécs, Hungary.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Denes
authors.affiliation: Department of Experimental Zoology and Neurobiology, University of Pécs, Pécs, Hungary.
authors.forename: Karmen
authors.initials: K
authors.lastname: Kovacs
authors.affiliation: Department of Experimental Zoology and Neurobiology, University of Pécs, Pécs, Hungary.
authors.forename: Orsolya
authors.initials: O
authors.lastname: Hideg
authors.affiliation: Department of Experimental Zoology and Neurobiology, University of Pécs, Pécs, Hungary.
authors.forename: Bence F
authors.initials: BF
authors.lastname: Szabo
authors.affiliation: Department of Experimental Zoology and Neurobiology, University of Pécs, Pécs, Hungary 3Neurobiology Research Group, János Szentágothai Research Center, Pécs, Hungary.
authors.forename: Robert
authors.initials: R
authors.lastname: Gabriel
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D018507:Gene Expression Regulation, Developmental; D023421:Models, Animal; D009024:Morphogenesis / Q000502:physiology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000096:biosynthesis / Q000235:genetics*; D012313:RNA / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D012313:RNA