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Developmental Genetics - Stefan Baumgartner

 Mechanisms of   bicoid   mRNA gradient formation in Drosophila. 

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The bicoid ( bcd) gene is a well-known maternal patterning gene that was discovered in a large-scale screen for female sterile mutants in Drosophila. Its genetic function was shown to be required maternally for the development of the larval head and thorax, while its activity was suggested to decline sharply with increasing distance from the anterior pole of a cleavage stage embryo (Frohnhöfer and Nüsslein-Volhard, Nature, 1986). In textbooks, the Bicoid protein serves as paradigm as the  first identified morphogen whose concentration gradient provides the initial positional information in the anterior half of the embryo where it differentially activates segmentation genes, particularly gap genes. The activity of the morphogen is expressed in a spectacular gradient of the Bicoid protein the concentration of which approximates an exponential decrease with distance from the anterior pole in the nuclei of syncytial blastoderm embryos (Driever and Nüsslein-Volhard, Cell, 1988). This gradient and its activity provided the first experimental proof of the French Flag model of pattern formation proposed by Wolpert (Wolpert, 1969). In this model, Wolpert reasoned that the spatial concentration gradient of a morphogen with its maximum at one end of a uniaxial field of cells could provide the positional information that uniquely specifies cellular fates.

Anchored in textbooks more than 20 years, the Bicoid protein gradient is generally believed to be established in the pre-blastoderm Drosophila embryo by the diffusion of Bicoid after translation of its maternal mRNA, which serves as a strictly localized source of Bicoid at the anterior pole (the so-called "SDD model"). However, already when proposed in 1988, this model ignored previous conflicting results (Frigerio et al., Cell 47, 735-746 (1986), which demonstrated that the Bicoid protein gradient is preceded by a bicoid mRNA gradient.

Recently, the SDD model, whose name refers to the localized synthesis , diffusion , and spatially uniform degradation of the Bicoid protein, has been subjected to a critical test (Gregor et al., Cell 130, 141-152 (2007). A series of interesting experiments, measuring the diffusion constant of Bicoid in the cortex of embryos, uncovered a serious difficulty of the model: the diffusion constant was too low by two orders of magnitude to explain the observation that the steady state of the Bicoid gradient profile is reached within 1.5 hours (Gregor et al., 2007), but the authors were unable to come up with a plausible explanation for their discovery, nor did they take into consideration that the mRNA gradient could have been the solution for their dilemna.

We extended our old results from 1986 by showing that the bicoid mRNA and protein gradient profiles are virtually identical at all times, which confirms our previous conclusion that the Bicoid gradient is produced by its mRNA rather than by diffusion (Spirov et al., (2009). Based on our observation that bicoid mRNA colocalizes with Staufen (Stau), we conclude that the bicoid mRNA gradient is formed by a novel mechanism of a quasi-random active transport of a Staufen- bicoid mRNA complex through a non-polar microtubular network, which confines the bicoid mRNA to the cortex of the embryo.

 

bicoid mrna protein

 

Refuting the SSD model of Bicoid gradient formation: The upper picture shows the distribution of the bicoid mRNA which reveals a gradient resembling that of the protein (lower picture) of a similar stage. This data and other evidences refute the current SSD model which states that the bicoid mRNA is located tightly at the anterior tip and which serves as the template for translation. Upon translation the protein should then diffuse to form the gradient.

This simple experiment proves that the SDD model cannot be correct, rather the protein gradient arises through an mRNA gradient and subsequent local translation of the Bicoid protein. A color scale to the right denotes the concentration of the mRNA and the protein.

 Check out two films on YouTube (click on film, watch in HD mode if possible): 

 

youtube film 1

  

 

youtube film 2

  

Original article: Alexander Spirov, Khalid Fahmy, Martina Schneider, Erich Frei, Markus Noll and Stefan Baumgartner: Formation of the bicoid morphogen gradient: an mRNA gradient dictates the protein gradient. (2009) In: Development, Volume 136, pp. 605-614.

Prospective MSc and PhD students:  To discuss possibilities to join the lab, please contact Stefan Baumgartner here

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