Pituitary adenylate cyclase-activating peptide (PACAP), a novel secretagogue, regulates secreted morphogens in newborn rat retina

Monika Lakk, Viktoria Denes, Karmen Kovacs, Orsolya Hideg, Bence F. Szabo, R. Gábriel

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

PURPOSE. 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. METHODS. 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. RESULTS. 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. CONCLUSIONS. 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.

Original languageEnglish
Pages (from-to)565-572
Number of pages8
JournalInvestigative Ophthalmology and Visual Science
Volume58
Issue number1
DOIs
Publication statusPublished - Jan 1 2017

Fingerprint

Pituitary Adenylate Cyclase-Activating Polypeptide Receptors
Adenylyl Cyclases
Retina
Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
Peptides
Receptors, Vasoactive Intestinal Peptide, Type II
Intravitreal Injections
Mitogens
Ganglia
Neurodegenerative Diseases
Dissection
Wistar Rats
Cell Differentiation
Up-Regulation
Central Nervous System
Western Blotting
Polymerase Chain Reaction
Messenger RNA
Injections
Proteins

Keywords

  • Bone morphogenic proteins
  • Development
  • Fibroblast growth factors
  • Hedgehogs
  • PACAP
  • Wnt1

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Pituitary adenylate cyclase-activating peptide (PACAP), a novel secretagogue, regulates secreted morphogens in newborn rat retina. / Lakk, Monika; Denes, Viktoria; Kovacs, Karmen; Hideg, Orsolya; Szabo, Bence F.; Gábriel, R.

In: Investigative Ophthalmology and Visual Science, Vol. 58, No. 1, 01.01.2017, p. 565-572.

Research output: Contribution to journalArticle

Lakk, Monika ; Denes, Viktoria ; Kovacs, Karmen ; Hideg, Orsolya ; Szabo, Bence F. ; Gábriel, R. / Pituitary adenylate cyclase-activating peptide (PACAP), a novel secretagogue, regulates secreted morphogens in newborn rat retina. In: Investigative Ophthalmology and Visual Science. 2017 ; Vol. 58, No. 1. pp. 565-572.
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AU - Hideg, Orsolya

AU - Szabo, Bence F.

AU - Gábriel, R.

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AB - PURPOSE. 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. METHODS. 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. RESULTS. 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. CONCLUSIONS. 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.

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