Andrew Oates - Molecular and cellular mechanisms of vertebrate segmentation

Previous and current research

Segmentation, or the use of serially repeated anatomical units is a fundamental feature of the body plan of many animal phyla. The segmented architecture of the vertebrate embryo and its relationship to the segmented structures of the adult has been appreciated for centuries, but the mechanisms establishing this spatial pattern during embryogenesis are only just being deciphered. In zebrafish embryos, as in all vertebrates, the reiterated skeleton and muscles of the adult are formed from the embryonic paraxial mesoderm. Beginning in the anterior of the embryo, this tissue progressively segments through the serial formation of epithelialized blocks of cells called somites from the more posterior, mesenchymal pre-somitic mesoderm (PSM). A remarkable insight into the control of vertebrate segmentation has come from recent findings of dynamic, wave-like gene expression patterns sweeping through the PSM prior to somite formation. These expression domains travel anteriorly through the PSM from the tailbud, then arrest at a location that predicts the site of a future somite boundary. These cyclic expression patterns are believed to represent the activity of coordinated biochemical oscillators in the cells of the PSM, and this oscillator has been dubbed the segmentation clock. Despite recent progress indicating that genes and proteins of the Delta/Notch signal transduction system are critical components of its structure, we do not yet understand the molecular mechanism driving its oscillation, the details of the oscillation dynamics, or the mechanism coordinating the oscillation phases of neighboring cells. Furthermore, we still do not understand how the output of this clock communicates timing information to the PSM cells that will respond morphologically by forming the regularly spaced boundaries of somites. By understanding the mechanism of the oscillator and how it generates boundaries in a tissue with changing geometry, we may learn about how the rate of sequential segment formation is coordinated with overall embryonic body growth. Indeed, how patterning and growth are coordinated during embryogenesis remains a central, and largely unexplored issue in biology. Further, from an evolutionary perspective, we may learn about the genetics of segment number change. Since changes in oscillator period would alter segment size, and therefore segment number, variation in oscillator structure may be a mechanism underlying the tremendous change in vertebral number seen with the phylum vertebrata e.g. ten segments in some frogs versus hundreds in snakes. Finally, the discovery of a new kind of biochemical oscillator is cause for great scientific excitement. All other biological oscillators, such as the circadian clock, appear to regulate the timing of biological phenomena, whereas the segmentation oscillator is used by the animal to measure distance. How does the embryo interpret the distance? Is the oscillator used in other patterning tasks? Is it also used for timing? What differences and similarities exist between the mechanisms of circadian and segmentation oscillators? We may expect that the comparison of the logical structure of these oscillators will reveal generalized principles of the organization and stability of biochemical networks that will guide efforts to interpret genome structure and expression.

A dorsal view of the developing zebrafish embryo reveals the amazing dynamical changes in cell positions and tissue morphology that accompany the rhythmic segmentation of the embryonic body axis - a process called somitogenesis.

The sequential formation of the periodic somite boundaries is driven by a genetic oscillator called the segmentation clock, which can be visualized by the dynamic gene expression patterns visible in the posterior end of the developing embryo.

Future prospects and goals

One of the main technical challenges in understanding a complex system such as this array of coordinated biochemical oscillators will be to develop methods for imaging and analyzing the oscillations in real time in living cells and embryos, a capability that does not currently exist. At present, we are limited to comparing snapshots of the spatial organization of mRNA expression in fixed embryos, or time series of the level of one protein in extracts from tissue culture cells. In parallel to the development of real time imaging techniques, quantitative mathematical models need to be built that allow a close conversation between theoretical and experimental sides of the investigation. Ultimately, these tools will serve side by side in probing the function of this oscillator with advanced embryological and genetic methods, thereby searching for explanations on levels ranging from molecules to cells to organisms.

Selected publications

Morelli LG , Ares S, Herrgen L, Schröter C, Jülicher F, Oates AC. (2009): Delayed coupling theory of vertebrate segmentation. HFSP Journal, 2009 February Vol 3(1): 55-66.

Schröter C, Herrgen L, Cardona A, Brouhard GJ, Feldman B, Oates AC. (2008): Dynamics of zebrafish somitogenesis. Dev Dyn. 2008 Mar;237(3): 545-53.

Riedel-Kruse IH, Müller C, Oates AC. (2007): Synchrony dynamics during initiation, failure, and rescue of the segmentation clock. Science. 2007 Sep 28;317(5846): 1911-5. Epub 2007 Aug 16.

Echeverri K, Oates AC. (2007): Coordination of symmetric cyclic gene expression during somitogenesis by Suppressor of Hairless involves regulation of retinoic acid catabolism. Dev Biol. Jan 15;301(2):388-403.

Shankaran SS, Sieger D, Schroter C, Czepe C, Pauly MC, Laplante MA, Becker TS, Oates AC, Gajewski M. (2007): Completing the set of h/E(spl) cyclic genes in zebrafish: her12 and her15 reveal novel modes of expression and contribute to the segmentation clock. Dev Biol. Jan 9; [Epub ahead of print]

Langenberg T, Dracz T, Oates AC, Heisenberg CP, Brand M. (2006): Analysis and visualization of cell movement in the developing zebrafish brain. Dev Dyn. Feb 22; [Epub ahead of print]

Oates AC, Rohde LA, Ho RK. (2005): Generation of segment polarity in the paraxial mesoderm of the zebrafish through a T-box-dependent inductive event. Dev Biol. Jul 1;283(1):204-14.

Oates AC, Mueller C, Ho RK. (2005): Cooperative function of deltaC and her7 in anterior segment formation. Dev Biol. Apr 1;280(1):133-49.

Oates, A. C and Ho, R. K. (2002): Hairy/E(spl)-related (Her) genes are central components of the segmentation oscillator and display redundancy with the Delta/Notch signaling pathway in the formation of anterior segmental boundaries in the zebrafish. Development, 15;129(12): 2929-2946

Andrew Oates

1998: PhD, Ludwig Institute for Cancer Research, University of Melbourne, Melbourne, Australia

1998-2001: Postdoctoral Fellow, Department of Molecular Biology, Princeton University

2001-2003: Postdoctoral Fellow, Department of Organismal Biology and Anatomy, University of Chicago

since 2003: Group leader, Max Planck Institute of Molecular Cell Biology and Genetics, Dresden