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News - Dec 05, 2012

Synchronous evolution of an odor biosynthesis pathway and behavioral response
Q. Li

Rodents use olfactory cues for species-specific behaviors. For example, mice emit odors to attract mates of the same species but not competitors of closely related species. This implies rapid evolution of olfactory signaling, although odors and chemosensory receptors involved are unknown. In recently published paper, the Liberles Lab identified a mouse chemosignal, trimethylamine, and its olfactory receptor, trace amine-associated receptor 5 (TAAR5), to be involved in species-specific social communication (Li et al, Current Biology, 2013). Abundant (>1,000-fold increased) and sex-dependent trimethylamine production arose de novo along the Mus lineage after divergence from Mus caroli. The two-step trimethylamine biosynthesis pathway involves synergy between commensal microflora and a sex-dependent liver enzyme, flavin-containing monooxygenase 3 (FMO3), which oxidizes trimethylamine. One key evolutionary alteration in this pathway is the recent acquisition in Mus of male-specific Fmo3 gene repression. Coincident with its evolving biosynthesis, trimethylamine evokes species-specific behaviors, attracting mice but repelling rats. Attraction to trimethylamine is abolished in TAAR5 knockout mice, and furthermore, attraction to mouse scent is impaired by enzymatic depletion of trimethylamine or TAAR5 knockout. TAAR5 is an evolutionarily conserved olfactory receptor required for a species-specific behavior. Synchronized changes in odor biosynthesis pathways and odor-evoked behaviors could ensure species-appropriate social interactions.

News - Nov 16, 2012

Substrate stiffness regulates cadherin-dependent collective migration through myosin-II contractility
R. Ng
A. Besser

The cellular microenvironment can affect cell behavior not only through paracrine and autocrine factors that bind to cellular receptors, but also through the mechanical properties of the tissue.  For example, it is known that the mechanical properties of the cell matrix, such as stiffness, can regulate the motility of single cells. However, it is not well understood how matrix stiffness affects collective migration, or the movement of groups of cells maintained by cell-cell adhesions. Collective migration plays critical roles in development, wound healing and cancer metastasis. To elucidate whether and how microenvironmental stiffness regulates collective migration, graduate student Rosa Ng (Brugge Lab) and postdoc Achim Besser (Danuser Lab) joined forces and conducted a systematic and quantitative study of epithelial sheet migration (Ng et al, Journal of Cell Biology, 2012).

Using a modified wound-healing assay, time-lapse microscopy and a custom cell migration tracking program, the migratory behaviors of >0.5 million MCF10A epithelial cells were monitored on substrates of various compliances. Individual cells comprising the epithelial sheets migrated faster, more persistently and more directionally on stiffer substrates. Most strikingly, increasing substrate stiffness promoted the coordination in cell movements during collective migration. On stiffer substrates, cell-cell coordination extended deeper from the wound edge into the cell sheet. Such propagation of cell-cell coordination was further correlated with myosin-II activity, in a manner dependent on cadherin-mediated cell-cell adhesions. Together, the results led to a physical model of collective migration, in which cell movements are regulated by microenvironmental stiffness modulation of cell contractility, and the coupling of cell contractility between cells by cadherin adhesions give rise to coordinated movements. The Brugge and Danuser laboratories are continuing to investigate the regulation of cell motility by the interplay between microenvironmental properties, cell contractility and cell-cell adhesions, which will be important for understanding developmental processes and cancer cell metastasis.