Purinergic Signals Regulate Daily Proliferative Activity in the Ciliary Marginal Zone of the Zebrafish Retina

MARIA JIMENA RICATTI; ARIADNA GABRIELA BATTISTA; MARÍA ZORRILLA ZUBILETE; MARIA PAULA FAILLACE

JOURNAL OF BIOLOGICAL RHYTHMS.

SAGE PUBLICATIONS INC

Año: 2011 p. 107 - 117

0748-7304

Regeneration and growth that occur in the adult teleost retina by neurogenesis have been helpful in identifying molecular and cellular mechanisms underlying cell proliferation and differentiation. In this report, we demonstrated that cell proliferative activity in the ciliary marginal zone (CMZ) of the adult zebrafish retina follows diurnal variations with highest values observed at the middle of the light phase. Cell proliferative activity in the CMZ did not show circadian variations when zebrafish were kept in constant darkness for four days. An ADPβS-treatment significantly enhanced cell division at night to the levels observed during the light phase, as assessed by in vivo BrdU incorporation in a period of 2 hours. Moreover, the diurnal increase in cell proliferation was completely abolished either when extracellular nucleotide levels or their extracellular hydrolysis by ectonucleoside triphosphate diphosphohydrolases (NTPDases) were significantly disrupted or when a selective antagonist of purinergic P2Y1 metabotropic receptors was intraocularly injected before BrdU exposure. Extracellular nucleotides and NTPDase action were also important for maintaining nocturnal low levels of proliferative activity in the CMZ. Finally, we showed that mRNA levels of NTPDases 1, 2 (three isoforms), and 3 as well as mRNA levels of P2Y1 receptor are present in the neural retina of zebrafish. NTPDases mRNA expression exhibited a two-fold increment in light versus dark conditions as assessed by quantitative RT-PCR whereas P2Y1 receptor mRNA levels did not show significant daily variations. This study demonstrates a key role for nucleotides, principally ADP as a paracrine signal, as well as for NTPDases, the plasma membrane-bound enzymes that control extracellular concentration of nucleotides, for the regulation of the proliferative activity in the CMZ, normally associated with retinal growth, throughout the light:dark cycle.