Mechanisms controlling cell cycle exit upon terminal differentiation

Abstract

Coordinating terminal differentiation with permanent exit from the cell cycle is crucial for proper organogenesis, yet how the cell cycle is blocked in differentiated tissues remains unclear. Important roles for retinoblastoma family proteins and Cyclin-dependent kinase inhibitors have been delineated, but in many cases it remains unclear what triggers cell cycle exit. This review focuses on describing recent advances in deciphering how terminal differentiation and exit from the cell cycle are coordinated.

Figure 1. Molecular stop signs: Multiple mechanisms prohibit cell cycle progression upon terminal differentiation

Negative regulators of the cell cycle act as blockades, preventing proliferation upon terminal differentiation. Recent research has identified new signals impinging on known blockades such as the retinoblastoma proteins (Rbs) and Cyclin dependent kinase inhibitors (CKIs), as well as new negative regulators such as Prospero-like homeobox transcrption factors (Pros), and a new post-mitotic role for the Anaphase Promoting Complex/Cyclosome (APC/C). Regulation can be at the level of transcription (dotted lines) or post-transcriptionally (solid lines). Recently identified pathways highlighted in blue are discussed in this review.

Figure 2. Terminal differentiation and cell cycle exit are separable

Although terminal differentiation and cell cycle exit are coordinated, in some contexts they are separable. A. For example a neuron in the late Drosophila retina can continue cycling and undergo mitosis (indicated by phosphohistone H3 in red) while maintaining characteristics of terminal differentiation, such as expression of Elav (in blue) and projection of an axon (cell membrane in green, indicated by an arrow) if both E2F and Cyclin/Cdk activities are kept high [25]. B. Hair cells of the mouse inner ear lacking Rb expression also continue cycling upon terminal differentiation, providing another example where differentiation and cell cycle exit are separable. Myo7A expression in red labels hair cells of the cochlea, while BrdU in green labels cells in S-phase. Co-labeled cells differentiate but continue into S-phase (arrow) C. Recorded transduction currents in Rb^−/− hair cells demonstrate mechanosensitivity [B and C adapted from 62].