MicroRNAs couple cell fate and developmental timing in retina.
Cell identity is acquired in different brain structures according to a stereotyped timing schedule, by accommodating the proliferation of multipotent progenitor cells and the generation of distinct types of mature nerve cells at precise times. However, the molecular mechanisms coupling the identity of a specific neuron and its birth date are poorly understood. In the neural retina, only late progenitor cells that divide slowly can become bipolar neurons, by the activation of otx2 and vsx1 genes. In Xenopus, we found that Xotx2 and Xvsx1 translation is inhibited in early progenitor cells that divide rapidly by a set of cell cycle-related microRNAs (miRNAs). Through expression and functional screenings, we selected 4 miRNAs--mir-129, mir-155, mir-214, and mir-222--that are highly expressed at early developmental stages in the embryonic retina and bind to the 3' UTR of Xotx2 and Xvsx1 mRNAs inhibiting their translation. The functional inactivation of these miRNAs in vivo releases the inhibition, supporting the generation of additional bipolar cells. We propose a model in which the proliferation rate and the age of a retinal progenitor are linked to each other and determine the progenitor fate through the activity of a set of miRNAs.
Decembrini
Sarah
S
Dipartimento di Biologia, Università di Pisa, Pisa 56100, Italy.
Bressan
Dario
D
Vignali
Robert
R
Pitto
Letizia
L
Mariotti
Sara
S
Rainaldi
Giuseppe
G
Wang
Xiumei
X
Evangelista
Monica
M
Barsacchi
Giuseppina
G
Cremisi
Federico
F
D000818:Animals; D019070:Cell Lineage; D049109:Cell Proliferation; D005136:Eye Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D035683:MicroRNAs / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000166:cytology; D051857:Otx Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012160:Retina / Q000196:embryology / Q000254:growth & development*; D051245:Retinal Bipolar Cells / Q000166:cytology; D013234:Stem Cells / Q000166:cytology; D014981:Xenopus; D029867:Xenopus Proteins / Q000037:antagonists & inhibitors / Q000235:genetics
D005136:Eye Proteins; D035683:MicroRNAs; D051857:Otx Transcription Factors; C497661:Otx2 protein, Xenopus; D012333:RNA, Messenger; D029867:Xenopus Proteins