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Aulehla GroupPublications

Dynamic signal encoding-from cells to organisms.
Sonnen, K.F. & Aulehla, A.
This is a review article.
Semin Cell Dev Biol. 2014 Jul 4. pii: S1084-9521(14)00192-X. doi:10.1016/j.semcdb.2014.06.019.
Encoding information at the level of signal dynamics allows cells to transmit information in a qualitatively and quantitatively defined and robust manner. Currently, a growing number of studies are unravelling the functional importance of dynamic signalling at the single cell level. In addition, first insights are emerging into how the principles of dynamic signal encoding apply to a multicellular context, such as development. In this review, we will first discuss general concepts of information transmission via signalling dynamics and recent experimental examples focusing on general underlying principles, including the role of intracellular network topologies. How multicellular organisms use temporal modulation of specific signalling pathways, such as signalling gradients or oscillations, to faithfully control cell fate decisions and pattern formation will also be addressed. Finally, we will consider how technical advancements in the detection and perturbation of signalling dynamics contribute to reshaping our understanding of dynamic signalling in developing organisms.
Europe PMC

Scaling of embryonic patterning based on phase-gradient encoding.
Lauschke, V.M., Tsiairis, C.D., Francois, P. & Aulehla, A.
Nature. 2013 Jan 3;493(7430):101-5. doi: 10.1038/nature11804. Epub 2012 Dec 19.
A fundamental feature of embryonic patterning is the ability to scale and maintain stable proportions despite changes in overall size, for instance during growth. A notable example occurs during vertebrate segment formation: after experimental reduction of embryo size, segments form proportionally smaller, and consequently, a normal number of segments is formed. Despite decades of experimental and theoretical work, the underlying mechanism remains unknown. More recently, ultradian oscillations in gene activity have been linked to the temporal control of segmentation; however, their implication in scaling remains elusive. Here we show that scaling of gene oscillation dynamics underlies segment scaling. To this end, we develop a new experimental model, an ex vivo primary cell culture assay that recapitulates mouse mesoderm patterning and segment scaling, in a quasi-monolayer of presomitic mesoderm cells (hereafter termed monolayer PSM or mPSM). Combined with real-time imaging of gene activity, this enabled us to quantify the gradual shift in the oscillation phase and thus determine the resulting phase gradient across the mPSM. Crucially, we show that this phase gradient scales by maintaining a fixed amplitude across mPSM of different lengths. We identify the slope of this phase gradient as a single predictive parameter for segment size, which functions in a size- and temperature-independent manner, revealing a hitherto unrecognized mechanism for scaling. Notably, in contrast to molecular gradients, a phase gradient describes the distribution of a dynamical cellular state. Thus, our phase-gradient scaling findings reveal a new level of dynamic information-processing, and provide evidence for the concept of phase-gradient encoding during embryonic patterning and scaling.
Europe PMC

Oscillating signaling pathways during embryonic development.
Aulehla, A. & Pourquie, O.
Curr Opin Cell Biol. 2008 Dec;20(6):632-7. Epub 2008 Oct 23.
Oscillatory signaling pathway activity during embryonic development was first identified in the process of vertebrate somite formation. In mouse, this process is thought to be largely controlled by a cyclic signaling network involving the Notch, FGF, and Wnt pathways. Surprisingly, several recent genetic studies reveal that the core oscillation pacemaker is unlikely to involve periodic activation by these pathways. The mechanism(s) responsible for the production of oscillatory gene activity during somite formation remains, therefore, to be discovered. Oscillatory signaling activity has recently been identified in developmental processes distinct from somite formation. Both the processes of limb development in chick embryos and the maintenance of neural progenitors in mouse embryos involve oscillatory gene activity related to the Notch pathway. These discoveries indicate that oscillatory signaling activities during embryonic development might serve a more general function than previously thought.
Europe PMC

A beta-catenin gradient links the clock and wavefront systems in mouse embryo segmentation.
Aulehla, A., Wiegraebe, W., Baubet, V., Wahl, M.B., Deng, C., Taketo, M., Lewandoski, M. & Pourquie, O.
Nat Cell Biol. 2008 Feb;10(2):186-93. Epub 2007 Dec 23.
Rhythmic production of vertebral precursors, the somites, causes bilateral columns of embryonic segments to form. This process involves a molecular oscillator--the segmentation clock--whose signal is translated into a spatial, periodic pattern by a complex signalling gradient system within the presomitic mesoderm (PSM). In mouse embryos, Wnt signalling has been implicated in both the clock and gradient mechanisms, but how the Wnt pathway can perform these two functions simultaneously remains unclear. Here, we use a yellow fluorescent protein (YFP)-based, real-time imaging system in mouse embryos to demonstrate that clock oscillations are independent of beta-catenin protein levels. In contrast, we show that the Wnt-signalling gradient is established through a nuclear beta-catenin protein gradient in the posterior PSM. This gradient of nuclear beta-catenin defines the size of the oscillatory field and controls key aspects of PSM maturation and segment formation, emphasizing the central role of Wnt signalling in this process.
Europe PMC

On periodicity and directionality of somitogenesis.
Aulehla, A. & Pourquie, O.
Anat Embryol (Berl). 2006 Dec;211 Suppl 1:3-8. Epub 2006 Sep 21.
It is currently thought that the mechanism underlying somitogenesis is linked to a molecular oscillator, the segmentation clock, and to gradients of signaling molecules within the paraxial mesoderm. Here, we review the current picture of this segmentation clock and gradients, and use this knowledge to critically ask: What is the basis for periodicity and directionality of somitogenesis?
Europe PMC

WNT signaling, in synergy with T/TBX6, controls Notch signaling by regulating Dll1 expression in the presomitic mesoderm of mouse embryos.
Hofmann, M., Schuster-Gossler, K., Watabe-Rudolph, M., Aulehla, A., Herrmann, B.G. & Gossler, A.
Genes Dev. 2004 Nov 15;18(22):2712-7.
Notch signaling in the presomitic mesoderm (psm) is critical for somite formation and patterning. Here, we show that WNT signals regulate transcription of the Notch ligand Dll1 in the tailbud and psm. LEF/TCF factors cooperate with TBX6 to activate transcription from the Dll1 promoter in vitro. Mutating either T or LEF/TCF sites in the Dll1 promoter abolishes reporter gene expression in vitro as well as in the tail bud and psm of transgenic embryos. Our results indicate that WNT activity, in synergy with TBX6, regulates Dll1 transcription and thereby controls Notch activity, somite formation, and patterning.
Europe PMC

Segmentation in vertebrates: clock and gradient finally joined.
Aulehla, A. & Herrmann, B.G.
Genes Dev. 2004 Sep 1;18(17):2060-7.
The vertebral column is derived from somites formed by segmentation of presomitic mesoderm, a fundamental process of vertebrate embryogenesis. Models on the mechanism controlling this process date back some three to four decades. Access to understanding the molecular control of somitogenesis has been gained only recently by the discovery of molecular oscillators (segmentation clock) and gradients of signaling molecules, as predicted by early models. The Notch signaling pathway is linked to the oscillator and plays a decisive role in inter- and intrasomitic boundary formation. An Fgf8 signaling gradient is involved in somite size control. And the (canonical) Wnt signaling pathway, driven by Wnt3a, appears to integrate clock and gradient in a global mechanism controlling the segmentation process. In this review, we discuss recent advances in understanding the molecular mechanism controlling somitogenesis.
Europe PMC

Wnt3a plays a major role in the segmentation clock controlling somitogenesis.
Aulehla, A., Wehrle, C., Brand-Saberi, B., Kemler, R., Gossler, A., Kanzler, B. & Herrmann, B.G.
Dev Cell. 2003 Mar;4(3):395-406.
The vertebral column derives from somites generated by segmentation of presomitic mesoderm (PSM). Somitogenesis involves a molecular oscillator, the segmentation clock, controlling periodic Notch signaling in the PSM. Here, we establish a novel link between Wnt/beta-catenin signaling and the segmentation clock. Axin2, a negative regulator of the Wnt pathway, is directly controlled by Wnt/beta-catenin and shows oscillating expression in the PSM, even when Notch signaling is impaired, alternating with Lfng expression. Moreover, Wnt3a is required for oscillating Notch signaling activity in the PSM. We propose that the segmentation clock is established by Wnt/beta-catenin signaling via a negative-feedback mechanism and that Wnt3a controls the segmentation process in vertebrates.
Europe PMC

Dynamic expression of lunatic fringe suggests a link between notch signaling and an autonomous cellular oscillator driving somite segmentation.
Aulehla, A. & Johnson, R.L.
Dev Biol. 1999 Mar 1;207(1):49-61.
The metameric organization of the vertebrate trunk is a characteristic feature of all members of this phylum. The origin of this metamerism can be traced to the division of paraxial mesoderm into individual units, termed somites, during embryonic development. Despite the identification of somites as the first overt sign of segmentation in vertebrates well over 100 years ago, the mechanism(s) underlying somite formation remain poorly understood. Recently, however, several genes have been identified which play prominent roles in orchestrating segmentation, including the novel secreted factor lunatic fringe. To gain further insight into the mechanism by which lunatic fringe controls somite development, we have conducted a thorough analysis of lunatic fringe expression in the unsegmented paraxial mesoderm of chick embryos. Here we report that lunatic fringe is expressed predominantly in somite -II, where somite I corresponds to the most recently formed somite and somite -I corresponds to the group of cells which will form the next somite. In addition, we show that lunatic fringe is expressed in a highly dynamic manner in the chick segmental plate prior to somite formation and that lunatic fringe expression cycles autonomously with a periodicity of somite formation. Moreover, the murine ortholog of lunatic fringe undergoes a similar cycling expression pattern in the presomitic mesoderm of somite stage mouse embryos. The demonstration of a dynamic periodic expression pattern suggests that lunatic fringe may function to integrate notch signaling to a cellular oscillator controlling somite segmentation.
Europe PMC

lunatic fringe is an essential mediator of somite segmentation and patterning.
Evrard, Y.A., Lun, Y., Aulehla, A., Gan, L. & Johnson, R.L.
Nature. 1998 Jul 23;394(6691):377-81.
The gene lunatic fringe encodes a secreted factor with significant sequence similarity to the Drosophila gene fringe. fringe has been proposed to function as a boundary-specific signalling molecule in the wing imaginal disc, where it is required to localize signalling activity by the protein Notch to the presumptive wing margin. By targeted disruption in mouse embryos, we show here that lunatic fringe is likewise required for boundary formation. lunatic fringe mutants fail to form boundaries between individual somites, the initial segmental unit of the vertebrate trunk. In addition, the normal alternating rostral-caudal pattern of the somitic mesoderm is disrupted, suggesting that intersomitic boundary formation and rostral-caudal patterning of somites are mechanistically linked by a process that requires lunatic fringe activity. As a result, the derivatives of the somitic mesoderm, especially the axial skeleton, are severely disorganized in lunatic fringe mutants. Taken together, our results demonstrate an essential function for a vertebrate fringe homologue and suggest a model in which lunatic fringe modulates Notch signalling in the segmental plate to regulate somitogenesis and rostral-caudal patterning of somites simultaneously.
Europe PMC

Multiple calvarial defects in lmx1b mutant mice.
Chen, H., Ovchinnikov, D., Pressman, C.L., Aulehla, A., Lun, Y. & Johnson, R.L.
Dev Genet. 1998;22(4):314-20.
The vertebrate cranial vault, or calvaria, forms during embryonic development from cranial mesenchyme of multiple embryonic origins. Inductive interactions are thought to specify the number and location of the calvarial bones, including interactions between the neuroepithelium and cranial mesenchyme. An important feature of calvarial development is the local inhibition of osteogenic potential which occurs between specific bones and results in the formation of the cranial sutures. These sutures allow for postnatal growth of the skull to accommodate postnatal increase in brain size. The molecular genetic mechanisms responsible for the patterning of individual calvarial bones and for the specification of the number and location of sutures are poorly understood at the molecular genetic level. Here we report on the function and expression pattern of the LIM-homeodomain gene, lmx1b, during calvarial development. Lmx1b is expressed in the neuroepithelium underlying portions of the developing skull and in cranial mesenchyme which contributes to portions of the cranial vault. Lmx1b is essential for proper patterning and morphogenesis of the calvaria since the supraoccipital and interparietal bones of lmx1b mutant mice are either missing or severely reduced. Moreover, lmx1b mutant mice have severely abnormal sutures between the frontal, parietal, and interparietal bones. Our results indicate that lmx1b is required for multiple events in calvarial development and suggest possible genetic interaction with other genes known to regulate skull development and suture formation.
Europe PMC