Timing the generation of distinct retinal cells by homeobox proteins.
The reason why different types of vertebrate nerve cells are generated in a particular sequence is still poorly understood. In the vertebrate retina, homeobox genes play a crucial role in establishing different cell identities. Here we provide evidence of a cellular clock that sequentially activates distinct homeobox genes in embryonic retinal cells, linking the identity of a retinal cell to its time of generation. By in situ expression analysis, we found that the three Xenopus homeobox genes Xotx5b, Xvsx1, and Xotx2 are initially transcribed but not translated in early retinal progenitors. Their translation requires cell cycle progression and is sequentially activated in photoreceptors (Xotx5b) and bipolar cells (Xvsx1 and Xotx2). Furthermore, by in vivo lipofection of "sensors" in which green fluorescent protein translation is under control of the 3' untranslated region (UTR), we found that the 3' UTRs of Xotx5b, Xvsx1, and Xotx2 are sufficient to drive a spatiotemporal pattern of translation matching that of the corresponding proteins and consistent with the time of generation of photoreceptors (Xotx5b) and bipolar cells (Xvsx1 and Xotx2). The block of cell cycle progression of single early retinal progenitors impairs their differentiation as photoreceptors and bipolar cells, but is rescued by the lipofection of Xotx5b and Xvsx1 coding sequences, respectively. This is the first evidence to our knowledge that vertebrate homeobox proteins can work as effectors of a cellular clock to establish distinct cell identities.
Decembrini
Sarah
S
Dipartimento di Biologia, Università degli Studi di Pisa, Pisa, Italy.
Andreazzoli
Massimiliano
M
Vignali
Robert
R
Barsacchi
Giuseppina
G
Cremisi
Federico
F
D000818:Animals; D001683:Biological Clocks / Q000235:genetics; D002453:Cell Cycle / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D019070:Cell Lineage; D002478:Cells, Cultured; D050684:E2F Transcription Factors / Q000378:metabolism / Q000502:physiology; D005136:Eye Proteins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D018398:Homeodomain Proteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology; D008969:Molecular Sequence Data; D051857:Otx Transcription Factors / Q000378:metabolism; D014176:Protein Biosynthesis; D012160:Retina / Q000166:cytology*; D051245:Retinal Bipolar Cells / Q000378:metabolism; D014162:Transfection; D029867:Xenopus Proteins / Q000378:metabolism; D014982:Xenopus laevis / Q000378:metabolism / Q000502:physiology; D000097642:GADD45 Proteins
D050684:E2F Transcription Factors; D005136:Eye Proteins; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051857:Otx Transcription Factors; D029867:Xenopus Proteins; D000097642:GADD45 Proteins; C416212:CRX protein, Xenopus; C497661:Otx2 protein, Xenopus; C491583:VSX1 protein, human