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Kimble Research
Critical Analysis

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The most basic question that may be asked in the field of development regulation in animals is, how does a single fertilized egg generate a multicellular organism which is characterized by a plethora of differentiated tissues?

The development from a fertilized egg to a multicellular organism involves cell division, organization of cells into tissues, aggregation of tissues into organs, and the interconnection of organs into organ systems. For these events to take place, a high degree of interaction and coordination between cells has to take place, a phenomenon typically known as signal transduction. Of equal importance are the events that lead to the development of the anterior-posterior and dorso-ventral axes in an embryo, for they help determine polarity in cells.

The scope of research activities in the Kimble lab touches on at least three of these developmental aspects, i.e., signal transduction and regulation of proliferation, translational control and regulation of cell fate, and organogenesis. However, this page will focus on tranlational regulation in C. elegans alone, in light of the fact that this aspect impacts development at various levels and is an area where Kimble has made various contributions.

Translational Regulation
Translational regulation is critical to three aspects of C. elegans development: (a) ontogenesis, (b) sex determination and (c) embryonic asymetry.

(a) Ontogenesis and the lin-14 gene
Ontogenesis has to do with the development of an organism from embryo to adult. C. elegans has to pass through four larval stages before reaching sexual maturity, L1, L2, L3 and L4. This progression from larval stages to adulthood depends on several genes including lin-14 and lin4. lin-14 is translationally regulated by lin-4 to achieve normal progression through adulthood via a most surprising molecular mechanism.

Indeed, lin-4 encodes two short RNAs (22 and 61 nucleotides) that do not seem to be able to generate any proteins. Instead, these RNA fragments are complementary to each of seven conserved elements in the 3'-UTR of lin-14. The resulting hybrid molecules are likely to be part of the trans-acting machinery that regulates lin-14. Proteins may also be involved but none have been identified as of yet.

This incipient model for the translational control of lin-14 proposes a temporal gradient of regulation by lin-4 where lin-14 is progressively repressed from stages L1 to L3, driving the transition from one stage to the next. The proponent of this model, Dr. Gary Ruvkun argues that the fact that there are seven consensus sequences in lin-14 3'-UTR that can form hybrids with lin-4 small RNAs can be construed as the mechanism by which the temporal regulation is effected. I.e., the time that takes the small RNAs to occupy seven position. Notwithstanding, this model seems to remain a point of controversy in the field. Kimble and a close colleague and collaborator Marvin Wikens are quick to point out that the hybrid molecules proposed in this molecule have not been detected by any direct methods at this point. A possible point of contention may be the method used by Ruvkun to test his "temporal gradient" hypothesis, which consisted of a reporter gene bearing 3 of the 7 consensus elements and which showed partial temporal gradient activity. A more exhaustive analysis of the literature would be required to discern this issue in its full scope.

(b) Translational Control and Sex Determination
The specification of sex in C. elegans (i.e., hermaphrodite vs. male) is determined by a group of sex determination genes. One of these genes, tra-2 was found to be regulated at the translational level (work done by Kimble and her collaborator Elizabeth Goodwin. See Goodwin and Kimble's seminal paper in Kimble noteworthy publications Ref. 7). It was found that mutants of tra-2 affected 28-bp tandem repeats located in the 3'-UTR of the gene. There are two of these tandem repeats, which are called DREs. Mutants may be affected on one or both of these DREs. A mutant having both DREs mutated will be less stable than a mutant having only one and so on. Under various criteria, it is concluded that these correspond to cis-acting negative regulatory elements. These analysis were based in part on a technique known as Synthesize reporter RNA in vitro.

Another gene fem-3 also appears to be regulated at the translational level. As with most of the other gene characterizations by Kimble and her collaborators, studies with fem-3 involved gain of function (gf) mutations. All gain of function mutations generated altered or removed nucleotides in a 5-bp region of the 3'-UTR that seems to be part of a cis-acting negative regulatory element. However, the exact mechanism by which the regulation of the gene is impacted is not understood. Work on this gene was done in collaboration with J. Ahringer. See one of Kimble and Ahringer's relevant papers in Kimble noteworthy publications Ref. 8.

(c) Translational Control and Embryonic Asymetry
Here Kimble's contribution has been significant in the characterization of a gene called glp-1. Two distinct aspects of translational control seem to be involved in the expression of glp-1. One is temporal: glp-1 mRNA is transiently silent in oocytes and one-celled embryos but is activated by the two- to four-cell stage. The second is spatial: glp-1 is translationally silent in the posterior portion of blastomeres but active in the anterior portion. Interestingly, the elements responsible for both control types reside in the 3'-UTR of the gene. Sequences responsible for spatial regulation lie in a 39-nucleotide element in the central region of the 3'-UTR, whereas those required for temporal control lie within an AU-rich region at the 3'-end of the 3'-UTR.

The current understanding of translational regulation is very limited at this point. One of the reasons is that very few translationaly regulated genes have been identified, and therefore, no generalizations can be made. For example, what are the characteristics of a cis-acting negative regulatory element. While Kimble and colleagues acknowledge that trans-acting elements are possibly involved in all these mechanisms, even less of these have been identified and their modes of action characterized. It is also likely that additional regulatory elements may exist at the 5'-UTR of genes. However, mutations in these regions seem more difficult to obtain. Because of all these reasons, the translational control field is still in its infancy and many revisions may have to be made in the way.

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Kimble Main Page
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Future direction in developmental regulation research

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