NIH Director's Pioneer Award

University Of California Berkeley, Berkeley CA

Investigators

Linked publications & trials

Abstract

A fundamental problem in cell and organism biology is to understand how intracellular structures are[unreadable] properly scaled to carry out their essential functions. I propose to explore the phenomenon of organelle[unreadable] size, documenting the changes that occur during development and tumorigenesis, and investigating the[unreadable] underlying molecular mechanisms. My laboratory will undertake a systematic analysis of cell and[unreadable] organelle scaling during embryonic development, evaluating nuclei, spindles and other compartments[unreadable] in Xenopus laevis, as the approximate 1 millimeter diameter egg rapidly cleaves to form smaller blastomeres,[unreadable] which by the 15th division are reduced to 40 microns across. Which structures have constant[unreadable] dimensions, and which change their size as cells become smaller? Other model organisms and cancer[unreadable] cells will be compared to generate a survey of organelle scaling in normal and abnormal cell growth[unreadable] states. Cytoplasmic egg and embryo extracts of X. laevis and the related, smaller frog X. tropicalis will[unreadable] be used to monitor nuclear, spindle and cellular compartment scaling in vitro. This approach is[unreadable] prompted by our observation that meiotic extracts prepared from X. tropicalis eggs generate spindles[unreadable] that are about 30% shorter than those in X. laevis reactions using the same chromosome source, and[unreadable] mixing experiments have revealed a dynamic, dose-dependent regulation of spindle size by[unreadable] cytoplasmic factors. We will determine which organelles in addition to the spindle are scaled in X.[unreadable] laevis and X. tropicalis extracts, and use activity-based assays to identify the factors responsible for the[unreadable] observed differences. Candidate factors will be tested for their roles in organelle scaling during[unreadable] development and cancer progression, and computational approaches applied to model our[unreadable] observations. These studies will provide novel insight into how cell/organelle scaling contributes to[unreadable] intracellular morphogenesis and cell division, processes essential for viability and development, and[unreadable] defective in human diseases including cancer.