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Metrics details. In this commentary, I will review the latest findings on the Bicoid Bcd morphogen in Drosophila , a paradigm for gradient formation taught to biology students for more than two decades. Initially proclaimed as a dogma in and later incorporated into the SDD model where the broad diffusion of Bcd throughout the embryo was the predominant step leading to gradient formation, the SDD model was irrefutable for more than two decades until first doubts were raised in regarding the diffusion properties of Bcd associated with the SDD model.

This led to re-thinking of the issue and the definition of a new model, termed the ARTS model which could explain most of the physical constraints that were inherently associated with the SDD model. In the ARTS model, gradient formation is mediated by the mRNA which is redistributed along cortical microtubules to form a mRNA gradient which is translated to form the protein gradient.

Contrary to the SDD model, there is no Bcd diffusion from the tip. I will critically compare the SDD and the ARTS models as well as other models, analyze the major differences, and highlight the path where Bcd is localized during early nuclear cycles. The Bicoid Bcd protein and its gradient Fig.

Not only was the morphogen gradient beautiful by appearance, it was also remarkable how the embryo managed to generate an anterior-posterior A-P gradient and a coordinate system based on information which initially is stored as a point source as maternal mRNA Fig. The gap genes, in turn, are expressed in broader domains along the A-P axis and control the so-called pair-rule genes which are usually expressed in 7 stripes [ 6 ].

These, in turn, control the segment polarity genes also referred to segmentation genes [ 7 ] that further subdivide the embryo into smaller units. Finally, homeotic genes are thought the maintain the status of the established segments [ 8 ]. Pictures represent midsagittal confocal planes or schematic drawings of embryos oriented with their dorsal side up and anterior to the left.

Relative intensities of the crude confocal pictures were converted to a color scale with values of 0— 8-bit , as shown in inserts of a and f , respectively. Nomenclature of nuclear cycles follows that of [ 28 ]. The mRNA gradient then serves as template for translation of the Bcd protein to form the protein gradient c , blue. The mRNA is translated to produce the Bcd protein d , blue which diffuses throughout the whole embryo e.

Please note that for both models, the start and end points are identical a , f , but they differ considerably in their mechanisms. The model proposed that the bcd mRNA stays strictly at the tip during all developmental stages Fig. The nuclei do not contribute to the shape of the gradient, but rather function as a tool to interpret the gradient [ 10 ]. Attempts to validate the model were inconclusive for a long time and it took almost two decades to realize that the diffusion constant of Bcd was far too low to move to the posterior [ 11 ] and that SDD model might contain conceptual errors.

One of the major drawbacks of the SSD model was its presumption that the Bcd protein diffused throughout the embryo Fig. This was fueled by studies where fluorescently labeled dextrane particles injected at the anterior pole were used to simulate the diffusion of Bcd [ 12 ]. In retrospect, it was a daring proposal, however, the constraints of this approach were clear from the very beginning. Nevertheless, the approach was too simplistic to assume that a protein would behave like a dextrane particle.

Subsequently, other reports measured higher diffusion rates [ 13 , 14 , 15 ], calculated to be high enough to explain the SDD diffusion model, corroborated by a recent biophysical model analysis [ 16 ]. One report showed that the mRNA briefly enters the yolk at nuclear cycle 4 [ 19 ]. In summary, while the start and end points of the two proposed mechanisms are identical Fig. In , a model was proposed to involve Bcd diffusion combined with nucleocytoplasmic shuttling, but no Bcd degradation [ 22 ].

The nuclei would serve as reversible traps that affect and slow down Bcd diffusion, while their increase in number with time would counteract the diffusive spread of Bcd. Notably, the Bcd gradient was predicted to be established before the nuclei migrate to the periphery, i. Moreover, the gradient was proposed to remain stationary during the remaining 4 nuclear cycles up to nc 14 when cellularization was reached.

To precisely monitor the path of Bcd movement during early development, a sensitive approach was developed that allowed for the study of the spatial Bcd movement during the early nuclear cycles using single confocal sections [ 20 ]. This study revealed, for the first time, that Bcd moved at the cortex of the egg but never entered the inner portion filled with yolk Fig.

Notably, the inner part of the egg, i. The results from this study immediately refuted the SDD model which predicted that Bcd would move throughout the yolk. If the egg was exposed to hypoxia, i. However, development resumed when oxygen was restored. The hypoxia technique permitted the monitoring of the movement of Bcd under prolonged sleeping conditions, i.

During this sleeping phase, Bcd still moved slowly at the cortex to the posterior. Again, the speed and location of Bcd movement was not compatible with the diffusion properties claimed by the SDD model [ 20 ], nor with that from the nucleocytoplasmic shuttle model [ 22 ]. This finding was unexpected, based on the previous knowledge of the diffusion of fluorescent dextrane particles which easily entered the yolk [ 12 ].

Data published concurrently by [ 20 ] reiterated the notion that the mechanism for Bcd movement was presumably far more complex than previously anticipated. Experiments demonstrated that embryos exposed to smaller drugs directed against major cytoarchitectural proteins such as microtubules MTs or actin, also affected Bcd movement Fig.

Intact MTs appeared to be indispensable for maintaining a non-permissive territory Fig. If actin was compromised, Bcd movement as well as its stability was affected leading to a substantially-altered Bcd pattern Fig. This data suggested that actin has a dual function for Bcd.

Cortical movement of Bcd and how drugs affect movement and stability of the Bcd protein. Relative intensities of the crude confocal pictures were converted to a color scale with values of 0— 8-bit , shown in insert of f. Nomenclature of nuclear cycles in green follows that of [ 28 ].

Red areas in a-d , f represents the yolk. The yolk part red serves as a non-permissive territory. Under hypoxic conditions, the yolk red still serves as non-permissive territory of Bcd movement. The yolk red still retains its non-permissiveness. The drug treatment data of [ 20 ] revealed that the inner part of the egg, i.

In vinblastine-treated embryos, the Bcd protein movement behaved exactly as the SDD model would have predicted, i. However, these are artificial conditions since embryos are not exposed to vinblastine in nature.

This observation also revealed several apparent weaknesses of the SDD model that were never before discussed. If the model was correct, why should the embryo translate a protein at the tip while the majority remains in the interior of the embryo, never reaching the blastoderm nuclei?

Secondly, how would an insect egg three times the size of Drosophila , e. Thirdly, why would nature choose such a difficult path from the tip through the yolk, and then back to the cortex to enter the blastoderm nuclei? Data on the content and structure of the inner yolk is limited, primarily due to microscopic constraints, because the laser of a confocal microscope cannot penetrate deeply into the optically dense yolk layer.

Actin microfilaments in the inner yolk were described [ 24 , 25 ], but require a more detailed description. For MTs, only the spindle apparatus during the nuclear cycles were bright enough to become visible [ 18 ].

Further, attempts to stain an internal MT network for visualizing axial expansion and cortical migration had apparently failed [ 26 , 27 ].

It is possible that the appearance of a MT-network involved in axial expansion and cortical expansion is nuclear cycle-dependent and consequently may be visible only for a fraction of the cycle, as was the case for the cortical MT network transporting the bcd mRNA along the cortex [ 18 ]. It is plausible to assume that the yolk contains a plethora of cytoskeletal elements that so far have escaped detection. For example, [ 28 ] described the existence of long fibrous materials, presumably of MT-origin, that were observed when embryos were squashed under certain salt conditions and the yolk content examined.

Currently, little data is known regarding the alternative splicing of the bcd gene resulting in 5 different isoforms, some of which have been characterized [ 29 , 30 ]. Of these, isoform A [ 31 ] represents a small homeobox-less isoform, amino acids aa in size which is expressed at vanishingly low levels [ 30 ] and therefore was likely undetected by the assay of [ 20 ]. The combination of these events allows for the creation of 4 larger Bcd isoforms of , , and aa, respectively [ 31 ].

However, given the prevalence of alternative splicing immediately upstream of the homeodomain, it was striking to learn that this splicing event was not found to occur in a close relative of D.

All studies using a bcd cDNA in the past were done based on the original c A likely scenario could be that the Bcd protein movement as well as its function could be largely dependent on isoforms, a question which has not been addressed.

Furthermore, the smallest isoform with aa likely has the capacity to travel faster to the posterior and may be the factor responsible for suppressing pole cell formation as demonstrated in [ 20 ]. Consistent with this observation is data that over-expression of the smallest Bcd isoform during oogenesis alters the segmental anlagen in the posterior and concomitantly suppresses pole cell-formation unpublished data.

The smallest Bcd isoform may also be responsible for the surprisingly robust signal resulting from hub activity of Bcd observed at the posterior end [ 35 ], despite the fact that only low concentrations of Bcd were measured at the posterior pole [ 36 ]. Unfortunately, the experimental setup of [ 35 ] did not allow to discriminate between the different Bcd isoforms to give a hint which isoform was actually detected.

To resolve the issue of Bcd isoform movement and function, sensitive isoform-specific antibodies would be required, experiments that would be technically challenging, but not impossible. This question was discussed by [ 11 ] in an effort to explain the low diffusion constant of Bcd.

Of these proteins, none were directly associated with a motor protein, thus, any interaction partner may require further proteins linking Bcd to a motor machinery which so far has not been detected. In my view, the strongest argument against active long-range transport of Bcd is the existence of the bcd mRNA gradient as the template for the protein gradient [ 1 , 17 ]. Moreover, the establishment of the mRNA gradient is fast enough to allow for the formation of the Bcd gradient which makes the involvement of active transport of Bcd largely superfluous.

Why does it make sense to observe Bcd residing and moving along the cortex and not moving towards the interior? Arguably, the most important finding is the cortical location of the mRNA Fig. From an energy point of view, it would be too costly to establish a path associated with the yolk first which would pose further problems on controlling the movement of Bcd.

These are the main reasons why today I believe in what I see. Structure of the segmentation gene paired and the Drosophila PRD gene set as part of a gene network. A gradient of bicoid protein in Drosophila embryos. Establishment of developmental precision and proportions in the early Drosophila embryo. Mutations affecting segment number and polarity in Drosophila. Gap gene regulatory dynamics evolve along a genotype network.

Mol Biol Evol. Clark E. Dynamic patterning by the Drosophila pair-rule network reconciles long-germ and short-germ segmentation. PLoS Biol. Ingham PW. Drosophila segment polarity mutants and the rediscovery of the hedgehog pathway genes. Curr Top Dev Biol.


Bicoid gradient formation and function in the Drosophila pre-syncytial blastoderm

Skip navigation. Bicoid is the protein product of a maternal-effect gene unique to flies of the genus Drosophila. A morphogen is a molecule that determines the fate and phenotype of a group of cells through a concentration gradient across that developing region. The bicoid gradient, which extends across the anterior-posterior axis of Drosophila embryos, organizes the head and thorax. The discovery of the first morphogen not only bolstered the study of embryonic pattern formation , but it also vindicated a concept more than one hundred years old. In Thomas Hunt Morgan hypothesized that a sort of stuff acted at different concentration levels to organize regeneration in hydroids , planarians, and annelids.


A Gradient of Bicoid Protein in Drosophila Embryos

The maternal gene bicoid bcd organizes anterior development in Drosophila. Its mRNA is localized at the anterior tip of the oocyte and early embryo. Antibodies raised against bcd fusion proteins recognize a kd doublet band in Western blots of extracts of hr old embryos. This protein is absent or reduced in embryonic extracts of nine of the 11 bcd alleles. The protein is concentrated in the nuclei of cleavage stage embryos.

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