The
Chx10 homeobox transcription factor gene is expressed in proliferating retinal progenitor cells throughout retinal development.
11 12 13 Expression is first detected in the presumptive neural retina of the invaginating optic vesicle. As progenitor cells exit the cell cycle and differentiate,
Chx10 expression is maintained only in the mitotic layer of the retina. By the time the retina is fully postmitotic
Chx10 expression persists only within bipolar cells of the inner nuclear layer. In the absence of
CHX10 in patients, or in the
ocular retardation (
Chx10 or-J/or-J ) mouse mutant carrying a null allele (Y176stop) of
Chx10, eye development is severely impaired.
11 12 The phenotype is characterized by microphthalmia, (small eye) and blindness. Histologic analysis of the
Chx10 or-J/or-J retina shows it to be thin and hypocellular. The optic nerve does not form, and the photoreceptors are abnormal with truncated outer segments
11 14 15 In the adult
Chx10 or-J/or-J eye, Müller glial cells and all types of retinal neurons have been detected, except bipolar cells, which are apparently absent.
11 Bromodeoxyuridine (BrdU) labeling of
Chx10 or-J/or-J shows reduced labeling indices in the peripheral retina compared with wild-type, although central retinal proliferation was not affected.
11 Expression of the transcription factors, retinoid-related orphan receptor-β and the forkhead gene
Foxn4, both normally expressed in retinal progenitors, show decreased expression in the
Chx10 or-J/or-J mutant,
16 17 whereas the cyclin-dependent kinase inhibitor, p27
kip1which is normally expressed transiently in retinal cells as they exit the cell cycle, is abnormally present in progenitors of the
Chx10 or-J/or-J mutant.
18 Crossing
Chx10 or-J/or-J mice with p27
kip1 null mice rescues much of the retinal size deficit, but bipolar cells are still absent.
18 In vitro, Chx10 protein has been shown to associate with the retinoblastoma protein and other members of the pRB gene family that are known to act as negative regulators of cell cycle progression.
19 Together these data suggest that
Chx10 has at least two essential roles in the developing retina: in retinal progenitor proliferation and in bipolar cell differentiation. The effect of the absence of
Chx10 on the expression of genes that are normally activated as cells leave the cell cycle and commit to a specific pathway of neuronal differentiation is unknown.