Transdifferentiation of the retina into pigmented cells in ocular retardation mice defines a new function of the homeodomain gene Chx10.
The homeodomain transcription factor Chx10 is one of the earliest markers of the developing retina. It is required for retinal progenitor cell proliferation as well as formation of bipolar cells, a type of retinal interneuron. or(J) (ocular retardation) mice, which are Chx10 null mutants, are microphthalmic and show expanded and abnormal peripheral structures, including the ciliary body. We show here, in a mixed genetic background, the progressive appearance of pigmented cells in the neural retina, concomitant with loss of expression of retinal markers. Fate mapping analysis using a multifunctional Chx10 BAC reporter mouse revealed this process to be direct transdifferentiation of retinal cells into pigmented cells. Microarray and in situ hybridization analyses revealed a complex program underlying the transdifferentiation. This program involved the expansion of expression of genes normally found only in the periphery into central regions of the eye. These genes included a transcription factor controlling pigmentation, Mitf, and the related factor Tfec (Tcfec -- Mouse Genome Informatics), which can activate a melanogenic gene expression program. Misexpression of Chx10 in the developing retinal pigmented epithelium (RPE) caused downregulation of Mitf, Tfec, and associated pigment markers, leading to a nonpigmented RPE. These data link Chx10 and Mitf to maintenance of the neural retina and RPE fates respectively. Further, they suggest a new role for Chx10 in maintenance of compartment boundaries in the peripheral retina.
Rowan
Sheldon
S
Department of Genetics and Howard Hughes Medical Institute, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Chen
C-M Amy
CM
Young
Tracy L
TL
Fisher
David E
DE
Cepko
Constance L
CL
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002642:Chick Embryo; D004268:DNA-Binding Proteins / Q000378:metabolism; D005124:Eye Abnormalities / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor; D010858:Pigmentation / Q000235:genetics / Q000502:physiology; D012160:Retina / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; C484069:Tcfec protein, mouse; D014157:Transcription Factors; C088975:Vsx2 protein, mouse