Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Stem Cell Reports. 2015 Jan 13;4(1):47-60. doi: 10.1016/j.stemcr.2014.11.001. Epub 2014 Dec 11.
Sensorineural hearing loss is caused by the loss of sensory hair cells and neurons of the inner ear. Once lost, these cell types are not replaced. Two genes expressed in the developing inner ear are c-Myc and Sox2. We created immortalized multipotent otic progenitor (iMOP) cells, a fate-restricted cell type, by transient expression of C-MYC in SOX2-expressing otic progenitor cells. This activated the endogenous C-MYC and amplified existing SOX2-dependent transcripts to promote self-renewal. RNA-seq and ChIP-seq analyses revealed that C-MYC and SOX2 occupy over 85% of the same promoters. C-MYC and SOX2 target genes include cyclin-dependent kinases that regulate cell-cycle progression. iMOP cells continually divide but retain the ability to differentiate into functional hair cells and neurons. We propose that SOX2 and C-MYC regulate cell-cycle progression of these cells and that downregulation of C-MYC expression after growth factor withdrawal serves as a molecular switch for differentiation.
感音神经性听力损失是由内耳感觉毛细胞和神经元的丧失引起的。一旦丧失,这些细胞类型就无法替代。在内耳发育过程中表达的两个基因是 c-Myc 和 Sox2。我们通过在表达 Sox2 的耳原基细胞中瞬时表达 C-MYC 来创建永生化多能耳原基(iMOP)细胞,这是一种命运受限的细胞类型。这激活了内源性 C-MYC 并扩增了现有的 Sox2 依赖性转录本,以促进自我更新。RNA-seq 和 ChIP-seq 分析表明,C-MYC 和 Sox2 占据了超过 85%的相同启动子。C-MYC 和 Sox2 的靶基因包括调节细胞周期进程的细胞周期蛋白依赖性激酶。iMOP 细胞不断分裂,但保留分化为功能性毛细胞和神经元的能力。我们提出 Sox2 和 C-MYC 调节这些细胞的细胞周期进程,并且生长因子撤出后 C-MYC 表达的下调是分化的分子开关。