Group of Cell Regulation

Unraveling the mysteries of life through the mysterious cytoskeleton

Figure 1: Diversity of higher-order septin assembly reconstituted in vitro. 1) Circular self-assembly. 2) Phospholipid-templated assembly, which can reshape the membrane. 3) Actomyosin-templated assembly, which may stabilize the contractile ring and stress fibers.

A common goal of science is the elucidation of the principles underlying self-organization of complex systems. In life science, a class of self-assembling protein polymers termed the cytoskeleton is central to this goal, because the cytoskeleton is the major determinant of cell shape and force. The actin ATPases and the tubulin GTPases, along with their counterpart motor proteins, have been well studied as key cytoskeletal components; however, the characteristics and functions of the septin GTPases remain elusive.

Due to their fundamental importance, either excess or deficiency of cytoskeletal proteins can affect cell shape and functions. Unless compensated, the cellular malfunctions manifest at the organismal level as lethality, morphological anomalies and/or functional defects. Such defects provide precious hints that help us understand complex biological systems, and hopefully control human diseases, e.g., neuropsychiatric disorders, neoplasia, infertility, infection.

Our approach is a combination of mouse reverse genetics, cell biology and biochemistry. First, we generate knockout or transgenic mice that lack or overexpress septins and/or related cytoskeletal regulators. Second, we explore defects (e.g., morphology, physiology including behavior, disease susceptibility) of these mice by multimodal screening. Third, we define the underlying molecular mechanisms of given defects via reductionistic (cell- , protein- and gene-based) approaches. By focusing on the mysteries of the cytoskeleton, we seek clues to unravel the mysteries of life.

Translation control and mRNA quality control

Gene expression is highly accurate due to quality-control systems that prevent the expression of potentially harmful protein products. We have shown that translation of the poly(A) tail results in repression of aberrant proteins from mRNAs that lack a stop codon; this repression is mediated by both inhibition of translation and proteasome-dependent nascent protein destabilization. The Upf1 protein also prevents the accumulation of aberrant truncated proteins by stimulating their degradation. We propose that translation arrest and protein degradation by the proteasome, in concert with rapid mRNA degradation, play crucial roles in preventing the expression of abnormal proteins derived from aberrant mRNAs.

Figure 2: Samples of diverse septin organizations and our approach. (From left) Ultrastructural analysis of septin clusters that organize membrane subdomains. Morphometry of developing neurons. The flagellar septin rings (green) in spermatozoa, discovered by reverse genetics. The septin cuffs (red) at the glia-neuron interface. Mouse genotyping at a glance.

Lab members