NIH Reporter #5R35GM150853-04

The coordination of cell size control and cell cycle regulation at developmental extremes

This award funds research on cell size control and cell cycle regulation in Drosophila development, focusing on mechanisms involving histone H3 and the nucleus to cytoplasm ratio during embryogenesis and oogenesis.

Description

A fundamental question in cell biology is how cells measure and maintain their characteristic sizes. We use two systems in Drosophila development to study cell size control that provide a natural system for uncoupling growth and division: embryogenesis and oogenesis. The early embryo is an extremely large cell that undergoes rapid divisions without cell growth, while the oocyte uses polyploid nurse cells to grow to a massive size without dividing. In the embryo, the final cell size is determined by the nucleus to cytoplasm ratio (N/C ratio). The N/C ratio controls a major developmental transition known as the mid-blastula transition (MBT) where the cell cycle stops and zygotic transcription initiates. Recently, we discovered a surprising mechanism for N/C-ratio sensing in the pre-MBT embryo. Hyper-abundant maternally provided histone H3 acts as a competitive inhibitor of the DNA-damage checkpoint kinase, Chk1, to prevent cell cycle slowing. As more nuclei are generated by the successive divisions, the pool of “free” histone H3 is imported into nuclei and incorporated into chromatin, releasing Chk1 inhibition to allow cell cycle slowing once a threshold N/C ratio is reached. In oogenesis, polyploid nurse cells generate the maternal supply of materials required for the egg and “dump” their contents into the oocyte to achieve the correct volume. Histone biogenesis appears to play a role in regulating progression through oogenesis, though the mechanism is unclear. Over the next five years, work will focus on: 1) how maternally provided H3 contributes to cell size sensing at the MBT; 2) how the N/C ratio affects nuclear and chromatin composition leading up to the MBT; and 3) extending models of cell size sensing to the growing egg chamber.

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