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30/12/2016 · Cisternal Progression

This paper represents my view of the development of the concept of cisternal progression-maturation over the last few decades, to date. It is not meant to be particularly technical or exhaustive, and it is not addressed only to the specialist. For more detailed information, readers are referred to the key references. The goal is mainly to stimulate discussion, for which the cisternal maturation model appears to be a very apt subject. Indeed, perhaps more than other models in biology, cisternal maturation has been accompanied from the beginning by a number of controversies. The reason for this is not completely clear to me. It might be because the model addresses issues at the historic core of modern cell biology; or because it challenges long-established views; or perhaps it is because its relevance actually goes beyond the field of intra-Golgi trafficking, as it might also apply to other trafficking steps (for instance, from early to late endosomes), and it gives rise to the concept of dynamic compartment identity, which is of broad relevance in cell biology. And last, but not least, the debate has suffered from uncertainties that are due to technical reasons: a few key questions cannot be addressed as directly as we would like, simply because today's microscopy imaging technologies do not yet possess the required resolution power (see below).

Is the cisternal maturation hypothesis correct

The Golgi is composed of membrane-bound stacks known as (singular: cisterna). Between four and eight are usually present; however, in some as many as sixty have been observed. Each cisterna comprises a flattened membrane disk, and carries Golgi enzymes to help or to modify cargo proteins that travel through them. They are found in both plant and animal cells.

Cisternal Maturation Hypothesis

"Cisternal Maturation Model" = a modified Progression Model

In the mid-1990s, however, the transport models were re-examined critically in a few different laboratories. On the one hand, there was a feeling that the complexity of the morphological observations in different cell types could not be explained by the simple vesicular model, and that other carriers (e.g. tubules) might be involved., On the other hand, and more importantly, there was the increasing recognition of the conservation of the basic cellular mechanisms across species, including those for transport. This made it difficult to continue dismissing the transport of scales as a mere ‘exception.’ Instead, it was realized that the old cisternal-progression model that could explain the transport of both small and large cargoes could be modified to also accommodate the very observations that had led to its demise; namely the fact that different Golgi cisternae have different, and apparently stable, enzymatic compositions.

To this end, it was necessary to introduce the idea of cisternal maturation. According to the maturation concept, cisternae change in composition, and hence, ‘identity’ through retrograde trafficking of the Golgi enzymes (and of other components) in lock-step with their progression (). This idea was discussed initially through personal exchanges between interested members of the scientific community, and then in a brief space of time, several groups published review articles in visible mainstream journals proposing the cisternal maturation idea. Other reviews with more refined models came later., It should be noted, however, that a version of the maturation model based on studies of the secretion of plant slimes had actually been presented earlier in a review in Protoplasma, though it had gone mostly unnoticed.

Live imaging of yeast Golgi cisternal maturation.

In the cisternal maturation hypothesis, the cisternae of the Golgi apparatus evolve.

The first study explicitly designed to test the cisternal progression-maturation model vis-a-vis the vesicular model was published in 1998. Bonfanti et al. used synchronized trafficking of procollagen in fibroblasts, accompanied by a series of stringent controls, to show that procollagen actually progresses in the form of aggregates from the cis to the trans Golgi in 10–15 minutes, without ever leaving the lumen of the cisternae. These observations could not be dismissed as incomplete or ascribed to an exceptional transport formula (see above) and, coupled with the constancy of the enzymatic compositions of cisternae, could only be interpreted as being due to the progression-maturation mechanism, although the maturation (compositional change) of the cisternae was not visualized in these experiments (see below).

As we know, this simple state of affairs was destined to change. The main culprit, among several other findings, was a series of observations documenting the presence of specific compositional differences between adjacent cisternae within a given stack (reviewed in ref. ). This showed that the Golgi cisternae are not similar to each other, as would be expected if the cisternae were simply progressing from cis to trans. For instance, it is now known that each cisterna has its own characteristic complement of glycosylating enzymes that differ from those of the other cisternae, and that those are arranged from cis to trans in the same order in which they are used in the sequence of glycosylation reactions that take place in the Golgi complex. The progression model could not explain how these enzymes remain in their cisternae while cargo proteins are swept forward (moreover, it had no role for the Golgi vesicles). This suggested a completely different organization of intra-Golgi transport. The cisternae must be stable compartments through which the cargo proteins are transported forward sequentially, by some dissociative carrier. Since the Golgi is surrounded by a number of spherical vesicles of regular size (60–70 nm in diameter), it was logical to propose that it is these vesicles that are the carriers that mediate trafficking from the proximal to the distal cisternae across the Golgi stack. This picture was not completely clear, though, because the transport of alga scales could not be mediated by these vesicles (as they are much larger than the Golgi vesicles); however, this was explained as an exception due to a ‘rare formula’ of transport present in a few evolutionarily distant organisms. Similarly, procollagen can be seen in the Golgi complex of fibroblasts in the form of aggregates that are much larger than vesicles; but again, this was set aside as an observation that would presumably be explained at later times. For instance, the large procollagen aggregates might not actually be transported; they might just be stationary bodies where a few procollagen molecules are occasionally trapped, while productive transport takes place in other parts of the cisternae (see ref. ). Thus, despite these discrepancies, the anterograde vesicular model gained broad acceptance. And during the molecular era of trafficking, the Golgi vesicles were isolated and their components were identified (COP-I subunits, Arf, etc.), along with many other proteins that are involved in transport, and were shown to be essential for the structure and function of the Golgi complex., These molecular findings strengthened the model of transport by anterograde vesicles that dominated the field for many years.

This effect can be explained by selective changes in cisternal maturation ..
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A brief history of the cisternal progression–maturation model

They therefore represented a turning point in the field, and initiated a period of rethinking of the transport mechanisms. Moreover, they carried important implications, quickly grasped by a few investigators, that impinged on the question as to whether cellular compartments may have dynamic (rather than stable) identities. They were followed initially by a series of counter-proposals that tended to support the vesicular model. In one, it was proposed that large cargoes, such as procollagen aggregates, can cross the Golgi stack within ‘megavesicles.’ This was based on experimental evidence that an artificial large polymeric cargo can be visualized in large peri-Golgi containers that are apparently separated from the Golgi cisternae in thin EM sections. However, a large number of 3D reconstructions of procollagen aggregates in the Golgi showed that these are never seen separated from the lumen of the cisternae; moreover, megavesicles were absent even under conditions (block of the fusion machinery) where vesicles can form but cannot fuse, i.e., under conditions where megavesicles should accumulate, if they existed. Another proposal was that the progression- maturation mechanism might represent a slow trafficking mode that is specialized for a few oversized cargo proteins, such as procollagen, while most of the other cargo proteins would follow a more common and fast route that would be mediated by the COPI vesicles. However, shortly after this proposal, it was shown that VSVG, a transmembrane protein that has been widely used in many laboratories as a common traffic marker, was transported through the Golgi complex in a fashion that was indistinguishable from that of procollagen. Thus, VSVG was also most likely moving by cisternal maturation, suggesting that this transport model applies broadly. Together with this, two reports came out: one that indicated that COP-I vesicles mediate the retrograde transport of the Golgi enzymes that are required for cisternal maturation (although this aspect remains controversial; see refs. and ), and the other that proposed a mechanism for the sorting of the Golgi enzymes into these vesicles. These results provided strong support for the maturation model.

tubules, or the process of cisternal progression/maturation

However, the most critical test came a few years later, with the direct demonstration by two independent laboratories (one of which had been among the early proponents of the model; see ref. ) that the Golgi cisternae indeed change composition in a fashion and at a rate that is consistent with cisternal maturation being the transport mechanism., These experiments were based on video microscopy in yeast, with the dynamic visualization of individual cis, medial and trans-Golgi cisternae, each tagged with fluorescent cisternal markers. Importantly, the use of yeast as the model organism was necessary because yeast cisternae are not arranged in stacks; rather, they move apparently freely in the cytosol, and can therefore be monitored individually in vivo by video-microscopy at the resolution that was currently available (stacked cisterna could not be resolved by the technology of the day). The use of yeast, however, also raised questions as to whether these conclusions that were drawn for yeast are actually applicable universally, to all eukaryotic cells. Given the degree of conservation of the fundamental cellular mechanisms found across species, including yeast and mammals, this is indeed likely to be the case. Nevertheless, experimental confirmation needs to be obtained. Another question left open by these experiments was due to the technical difficulty of visualizing fluorescent cargo proteins together with the cisternal markers. Because the cargo could not be visualized, an objection was that the maturing cisternae being analyzed might not be involved in cargo transport. Again, this appears very unlikely; however, experimental confirmation is desirable. In any case, and in spite of the difficulties, these direct observations of cisternal maturation provided essential and direct support for this model. In fact, together with the results on procollagen transport in fibroblasts, these data represent the experimental foundation of the cisternal progression-maturation concept.

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