Molecular Neurobiology

, Volume 54, Issue 7, pp 5142–5155 | Cite as

Adenine Nucleotides Control Proliferation In Vivo of Rat Retinal Progenitors by P2Y1 Receptor

  • Luana de Almeida-Pereira
  • Camila Feitosa Magalhães
  • Marinna Garcia Repossi
  • Maria Luiza Prates Thorstenberg
  • Alfred Sholl-Franco
  • Robson Coutinho-Silva
  • Ana Lucia Marques Ventura
  • Lucianne Fragel-Madeira


Previous studies demonstrated that exogenous ATP is able to regulate proliferation of retinal progenitor cells (RPCs) in vitro possibly via P2Y1 receptor, a G protein-coupled receptor. Here, we evaluated the function of adenine nucleotides in vivo during retinal development of newborn rats. Intravitreal injection of apyrase, an enzyme that hydrolyzes nucleotides, reduced cell proliferation in retinas at postnatal day 2 (P2). This decrease was reversed when retinas were treated together with ATPγ-S or ADPβ-S, two hydrolysis-resistant analogs of ATP and ADP, respectively. During early postnatal days (P0 to P5), an increase in ectonucleotidase (E-NTPDase) activity was observed in the retina, suggesting a decrease in the availability of adenine nucleotides, coinciding with the end of proliferation. Interestingly, intravitreal injection of the E-NTPDase inhibitor ARL67156 increased proliferation by around 60 % at P5 rats. Furthermore, immunolabeling against P2Y1 receptor was observed overall in retina layers from P2 rats, including proliferating Ki-67-positive cells in the neuroblastic layer (NBL), suggesting that this receptor could be responsible for the action of adenine nucleotides upon proliferation of RPCs. Accordingly, intravitreal injection of MRS2179, a selective antagonist of P2Y1 receptors, reduced cell proliferation by approximately 20 % in P2 rats. Moreover, treatment with MRS 2179 caused an increase in p57KIP2 and cyclin D1 expression, a reduction in cyclin E and Rb phosphorylated expression and in BrdU-positive cell number. These data suggest that the adenine nucleotides modulate the proliferation of rat RPCs via activation of P2Y1 receptors regulating transition from G1 to S phase of the cell cycle.


Retina Development Proliferation Purines P2Y1 receptor 


Compliance with Ethical Standards

All procedures complied with the Guidelines for the Care and Use of Laboratory Animals, from the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research, and were approved by the Committee for the Use of Experimental Animals of the Fluminense Federal University by protocol number 547/2014.

Supplementary material

12035_2016_59_Fig6_ESM.jpg (2 kb)
Figure S1

P2Y1 receptor identification in a newborn rat retina. a, b and c Negative control (a DAPI—blue, b without anti-P2Y1 primary antibody—red, c merge). d, e and f P2Y1 immunostaining (d DAPI—blue, e P2Y1—red, f merge). The P2Y1 receptor was found in all layers at P2 rat retina. In the GCL and IPL, it was uniformly distributed at the cell surface, but in the NBL, we observed a dotted staining to P2Y1 receptor. The retina photomicrography represents a 400× magnification under indirect fluorescence using a Leica microscope (DM2500). GCL = Ganglion Cell Layer; IPL = Inner Plexiform Layer; NBL = Neuroblastic Layer; Scale bar = 100 μM. (JPEG 1 kb)

12035_2016_59_MOESM1_ESM.tif (494 kb)
High Resolution Image (TIFF 494 kb)
12035_2016_59_Fig7_ESM.jpg (3 kb)
Figure S2

The treatment of 100 μM MRS 2179 did not induce cell death at rat retina. Neutral red staining at P2 rat retina control and treated with 100 μM MRS 2179 at different survival times. At any survival time, there was no observed difference in the amount of pyknotic nuclei between the control and treated animals. a Control 3 h; b 100 μM MRS 2179 3 h; c Control 6 h; d 100 μM MRS 2179 6 h; e Control 12 h; f 100 μM MRS 2179 12 h; g Control 16 h; h 100 μM MRS 2179 16 h; i Control 20 h; j 100 μM MRS 2179 20 h. The retina photomicrographs represent 400× magnification under differential interference contrast using a Leica microscope (DM2500). GCL = Ganglion Cell Layer; IPL = Inner Plexiform Layer; NBL = Neuroblastic Layer. Scale bar = 50 μm (JPEG 2 kb)

12035_2016_59_MOESM2_ESM.tif (1 mb)
High Resolution Image (TIFF 1033 kb)


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Luana de Almeida-Pereira
    • 1
  • Camila Feitosa Magalhães
    • 1
  • Marinna Garcia Repossi
    • 1
  • Maria Luiza Prates Thorstenberg
    • 2
  • Alfred Sholl-Franco
    • 2
  • Robson Coutinho-Silva
    • 2
  • Ana Lucia Marques Ventura
    • 1
  • Lucianne Fragel-Madeira
    • 1
    • 3
  1. 1.Department of Neurobiology, Institute of BiologyFluminense Federal UniversityNiteróiBrazil
  2. 2.Institute of Biophysics Carlos Chagas FilhoFederal University of Rio de JaneiroRio de JaneiroBrazil
  3. 3.Laboratório de Desenvolvimento e Regeneração Neural, Departmento de NeurobiologiaUniversidade Federal FluminenseNiteróiBrazil

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