PROJECT TITLE: Smc1 and the Cohesin Complex in Retinal Development and Disease: A New Mouse Model of Photoreceptor Degeneration
ABSTRACT: Myc proto-oncogenes regulate diverse cellular processes during development, but their roles during morphogenesis of specific tissues are not fully understood. This study found that c-myc regulates cell proliferation in mouse lens development and previous genome-wide studies suggested functional roles for N-myc in developing lens. The role of N-myc was examined in mouse lens development. Genetic inaction of N-myc in the surface ectoderm or lens vesicle impaired eye and lens growth, while “late” inactivation in lens fibers had no effect. Unexpectedly, defective growth of N-myc-deficient lenses was not associated with alterations in lens progenitor cell proliferation or survival. Notably, N-myc-deficient lens exhibited a delay in degradation of DNA in terminally differentiating lens fiber cells. RNA-sequencing analysis of N-myc-deficient lenses identified a cohort of down-regulated genes associated with fiber cell differentiation that included DNaseIIβ. Further, an integrated analysis of differentially expressed genes in N-myc-deficient lens using normal lens expression patterns of iSyTE, N-myc-binding motif analysis and molecular interaction data from the String database led to the derivation of an N-myc-based gene regulatory network in the lens. Finally, analysis of N-myc and c-myc double-deficient lens demonstrated that these Myc genes cooperate to drive lens growth prior to lens vesicle stage. Together, these findings provide evidence for exclusive and cooperative functions of Myc transcription factors in mouse lens development and identify novel mechanisms by which N-myc regulates cell differentiation during eye morphogenesis.
Dr. Martins is an IRRF-Funded scientist at the Federal University of Rio de Janeiro, where he is an Assistant Professor. His funded project, Smc1 and the Cohesin Complex in Retinal Development and Disease: A New Mouse Model of Photoreceptor Degeneration, has resulted in a published paper in Developmental Biology, “N-myc regulates growth and fiber cell differentiation in lens development.”
TERMS: MYC – an immediate early response gene downstream of many ligand-membrane receptor complexes (Armelin et al., 1984; Kelly et al., 1983) binding to 10%-15% of genomic loci in mammals.
Oncogene – defined as a gene that encodes a protein that is capable of transforming cells in cultures or inducing cancer in animals.
Morphogenesis – can be defined as the processes that are responsible for producing the complex shapes of adults from the simple ball of cells that derives from division of the fertilized egg. (On-line Medical Dictionary, © 1997-98 Academic Medical Publishing & CancerWEB).
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