Abstract
Myc protooncogenes play important roles in the regulation of cell proliferation, growth, differentiation and survival during development. In various developing organs, c-myc has been shown to control the expression of cell cycle regulators and its misregulated expression is detected in many human tumors. Here, we show that c-myc gene (Myc) is highly expressed in developing mouse lens. Targeted deletion of c-myc gene from head surface ectoderm dramatically impaired ocular organogenesis, resulting in severe microphtalmia, defective anterior segment development, formation of a lens stalk and/or aphakia. In particular, lenses lacking c-myc presented thinner epithelial cell layer and growth impairment that was detectable soon after its inactivation. Defective development of c-myc-null lens was not caused by increased cell death of lens progenitor cells. Instead, c-myc loss reduced cell proliferation, what was associated with an ectopic expression of Prox1 and p27Kip1 proteins within epithelial cells. Interestingly, a sharp decrease in the expression of the forkhead box transcription factor Foxe3 was also observed following c-myc inactivation. These data represent the first description of the physiological roles played by a Myc family member in mouse lens development. Our findings support the conclusion that c-myc regulates the proliferation of lens epithelial cells in vivo and may, directly or indirectly, modulate the expression of classical cell cycle regulators in developing mouse lens.
Highlights
Complex developmental processes must be carefully orchestrated for the correct formation of the vertebrate eye
We found several lines of evidence that the protooncogene c-myc is required for proper development of the lens in vivo
We show that the amount of c-myc (Myc) transcripts sharply decreases during lens embryonic development and remain at lower levels from E17.5 through adulthood
Summary
Complex developmental processes must be carefully orchestrated for the correct formation of the vertebrate eye. Concomitant with the coordinated growth of the developing lens and retina, the formation of a functionally mature eye depends on the precise coordination of cell proliferation, cell cycle exit and cell differentiation within these structures. In the past several years, a lot has been learned about the mechanisms that regulate these events, including the cell-extrinsic cues, such as growth factors, and cell-intrinsic factors, including cell cycle proteins and transcriptional regulators. Several homeodomaincontaining proteins that act as transcription factors were identified and characterized as regulators of cell proliferation and cell differentiation in the developing lens. Some recent studies addressed how these transcriptional networks functionally interact in vivo to regulate cell proliferation during lens ontogenesis [6,7]
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