Pleiotropic functions of pituitary adenylyl cyclase-activating polypeptide on retinal ontogenesis: involvement of KLF4 in the control of progenitor cell proliferation.
We showed previously that the neuropeptide pituitary adenylyl cyclase-activating polypeptide (PACAP) negatively regulates proliferation of postnatal rat retinal progenitor cells through the downregulation of cyclin D1 in a cAMP/protein kinase A dependent manner. In the present study, we describe by microarray analysis several putative PACAP targets regulated by different transcription factor families. One of these families is the Sp/Klf family of transcriptional factors capable of regulating cyclin D1, and among members, we demonstrate by immunocytochemistry that KLF4 is expressed throughout rat retinal development by retinal progenitor cells and in most differentiated cell types. Using retinal explants preparations, PACAP treatment can transiently increase Klf4 mRNA levels; from electrophoretic mobility shift assays, PACAP is also able to increase the nuclear KLF4 content. From these results, we suggest that KLF4 may be involved in the anti-proliferative effects of PACAP as one mechanism regulating progenitor cell transition from proliferation to differentiation throughout retinal development.
Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Av. Carlos Chagas Filho, 373, Edifício do Centro de Ciencias da Saude, Bloco G, Cidade Universitaria, Ilha do Fundão, 21941-902, Rio de Janeiro, Brazil.
Brian
B
Njaine
Maurício
M
Rocha-Martins
Carlos H
CH
Vieira-Vieira
Luiz D Barbosa
LD
De-Melo
Rafael
R
Linden
Karen
K
Braas
Victor
V
May
Rodrigo A P
RA
Martins
Mariana S
MS
Silveira
D000818:Animals; D049109:Cell Proliferation; D058685:Genetic Pleiotropy; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*
C000715469:Klf4 protein, rat; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide