“The Reaper comes to All Organisms ?”
What is the genetic component to the control of embryo development and how can we study development in such a complex system such as a human?
It has been long recognised that any 'organisms’ physical characteristics are governed by its genetic make-up. It is easy enough to see how a persons eye colour for instance is determined by certain genes, but how does the body know how to make the eye in the first place or even where to put the eye! There has been a great lack of understanding how these early stages of development are initiated and governed. Much of our understanding has been from the study of genetic defects in simple model organisms, this knowledge can then be applied to mare complex organisms and comparisons examined.
Enter the fruit fly
Genetic analysis in the fruit fly led to the characterisation of an important class of genes, the homeotic selector genes, which play a critical role in orchestrating fly development (2). Mutations in these genes cause one body part to be converted to another, this shows that the proteins they encode control the developmental switches (3). Sequencing work was carried out on several of these genes in the early 80’s and it was found that they all had a very similar stretch of 60 amino acids, which now defines this class of protein produced and is called its homeodomain. Once further work on the homeodomain was carried out it was found that the protein contained a helix-turn-helix motif related to that of bacterial gene regulatory proteins. This demonstrates the importance of using simple model organisms as many genes governing fundamental biological processes are highly conserved and often use similar mechanisms; thus giving a good starting point and insight in to how a more complex organism such as a human carries out the same process without the further complications cause by such a complex organism. Carrol, S.B (1995) gave further weight to this argument by showing it is possible to transfer a homeotic gene from a man to the embryo of a fruit fly, where it can perform some of the functions that the corresponding Drosophila gene normally executes. This principal is true of many systems including embryonic development as shown below with particular interest given to drosophila (fruit fly) a frequently used model organism.
How do genes control the embryo?
Nüsslein-volhard and Wieschaus (1980) gave much of the early indications that the eggs own genes control embryonic development. They are divided in to three functional groups. Firstly the gap-genes lay the foundation of a rough body plan along the head to tail axis. Secondly the pair rule-genes govern formation of every second body segment. Finally the segment polarity-genes refine the head to tail polarity of each individual segment(10), meaning that the head end and the tail end of a segment look different. These are expressed in three waves all being expressed in sequence within hours(8).
Homeotic genes control the further specialisation of larval segments. Bithorax and Antennapedia are the two complexes of homeotic genes in the fly’s DNA (fig.1). Edward B. Lewis showed that the genes controlling the bithorax along the DNA are arranged in the same general order as their expression pattern along the head to tail axis.
Edward B. Lewis described in his co-linearity principle showed that genetic expression domains overlap and the first gene in the complex becomes active a little earlier than the second etc. This is shown in fig.2 by the black bars under the fly embryo. Other research showed the homeotic genes of the fly are homologous to homeotic genes in other animals i.e. mice. This means that the genetic control mechanisms have been roughly unchanged through 650 million years of evolution (4). The order of activation of these genes is equally very important as shown when a mutant was studied with four wings and no halteres (balance organs).
Lewis found that the extra pair of wings was due to a duplication of an entire body segment, the 2nd thoratic segment(8). Inactivation of the first gene of the bithorax-complex caused other homeotic genes to re-specify the 3rd thoratic segment in to one that forms wings instead of halteres. A possible prediction from findings such as these in connection with work done by Carrol (1995) could be that very specific homeotic genes may control the positioning of our rib design with its specific pattern.
What has Death got to do with Life?
Along with activating specific genes to promote growth, there must also be a counterforce to bring about balanced growth. This is brought about through a process known as apoptosis or ‘programmed cell death’. A gene has been discovered which is essential in these early stages for cell death, ironically named the reaper gene.
The reaper protein is made up of 65 amino acids and is responsible for the co-ordination of programmed cell death to ensure the correct cell formations during development (Abrams 1993).
In drosophila the earliest normal appearance of cell death is in three places within the head leading to normal development, the dorsal cephalic region, the gnathal segments and in the clypeolabrum. This happens in Bownes stage No. 11 (approx. 320-440 minutes after fertilization). Also the genes grim and wrinkled are involved in head apoptosis processes (Abrams 1993). Grim seems to be able to induce apoptosis in certain situations without reaper, so the grim reaper may be forming two parallel yet linked death programs.
Mutants of reaper contain many extra cells and fail to hatch, but other development seems normal. The fly is born with approx. 25 abdominal Neuroblast cells, but only 6 eventually produce neurons in the imaginal ganglia. In reaper mutants 20 or more cells are found in some abdominal segments. A similar increase is found in the number of cells in the larval photoreceptor organ(12).
This gene was found to have a homologue in C.elegans as documented by the laboratory journals of Qiong Liu et al. Therefore the reaper may have a homologue in many more organisms, including humans.
So it seems that life and death really is in true equilibrium, not only in populations but also inside every living organism from the first moments of life with different organisms having very similar regulatory systems.
(p.s. just in case you missed the play on words - Grim and Reaper are two of the important genes discussed, hence 'The Reaper comes to us all').
- Abrams, J. M., et al. (1993). Programmed cell death during Drosophila embryogenesis. Development 117:29-43
- Alberts, B., et al. (1994). Molecular Biology of the Cell. Garland Publishing Inc.
- Brook, W. Control of Segmental Identity in Drosophila : Homeotic Genes. Department of Medical Biochemistry, University of Calgary. http://www.ucalgary.ca
- Carrol, S.B. (1995) Homeotic Genes and the Evolution of Arthropods and Chordates. Nature 376, pp.479-485.
- Lambin, A.F., Steller, H. Control of the Cell Death Gene Reaper in Response to Cell Death –Induced Stimuli. Depts. of Biology and Brain and Cognitive Sciences, MIT, Cambridge, MA.
- Lawrence, P. (1992) The Making of a Fly. Blackwell Scientific Publications. Oxford Press.
- Lodish, H., et al. (1978) Molecular Cell Biology, 3rd Ed. Molecular Cell Biology. Scientific AmericanBooks. New York.
- Lewis, E.B. (1978) A Gene Complex Controlling Segmentation in Drosophila. Nature 276, pp.565-570.
- Liu, Q., Hengartner. (2000). Effect of Drosophila Cell Death Gene Reaper on Programmed Cell Death in C. Elegans. Cold Spring Harbour Laboratory, Cold Spring Harbor, N.Y.www.devbio-mac.1.ucsf.edu.
- Nüsslein-Volhard, C. Weischaus, E.F. (1980) Mutations Affecting Segment Number and Polarity in Drosophila. Nature 287, pp.795-801.
- Stryer, L. (1995). Biochemistry 4th edition. W.H. Freeman and company Ltd.
- White, K., et al. (1994). Genetic control of programmed cell death in Drosophila. Science 264: 677-83.