How do two neighboring stem cells in the blastocyst end up becoming completely different mature cell types? This has been a question of ongoing interest for researchers who study embryonic development. These cells theoretically have the same genetic code, and are indistinguishable at the blastocyst state, so what caused them to pursue such dramatically divergent careers in life?
Researchers from UC San Diego and Sandford Burnham Medical Research Institute published an article in Genes and Development that sheds light on the enigma of cell destiny. Colas et al. sifted through hundreds of sequences of non-coding microRNA to determine whether it regulates stem cell destiny. They thought to do this because among the many other functions of this non-protein coding region of the genome, microRNA seems to play a key role in regulating various cellular processes. They found two factors that regulate mesoderm, ectoderm, and endoderm formation, which is the initial step in embryonic development after implantation.
By way of a little biology review, we are talking about mammal embryos. Not all organisms develop an ectoderm, mesoderm, and endoderm. Some develop two of these, others do not. Colas et al. looked at mouse embryos as their model organism, although they did compare them to frog and zebra fish counterparts. Once the cells have been assigned to either the ectoderm, mesoderm, or endoderm layer, they will only become certain cell types. The endoderm tends to form the major organs involved in the digestive system, about half of the major components of the urinary system, as well as the lungs and trachea. The mesoderm tends to form the skeletal structure, skin and connective tissue, the other half of the urinary system, and the circulatory system. The ectoderm forms the nervous system and other parts such as tooth enamel, the lining of the mouth and nostrils, and hair and nails.
MicroRNAs do not code for proteins, but they have been found to regulate translation of messenger RNA, which does code for proteins. Since MicroRNAs serve as regulators in other capacities, Colas wanted to see if they were the culprits in regulating embryological development. The team found that two factors, let-7 and miR-18, were key players in this regulation. They give a detailed breakdown as follows:
High-throughput functional screening revealed two families, let-7 and miR-18, that promote mesoderm differentiation at the expense of endoderm. let-7 and miR-18 control germ layer fate by negatively regulating TGFβ/Nodal signaling by directly targeting Acvr1b and Smad2, respectively. Interestingly, the function of let-7 is not restricted to mesoderm; it is also expressed in the emerging ectoderm and mesoderm of mouse and Xenopus [frog] embryos, where it prevents these tissues from becoming endoderm.Notice that let-7 plays a couple of different roles in the body, meaning that it is employed for more than one complex regulatory task. The authors found that the role these regulatory families play helps to establish a border, or layer, that separates the different germ layers. They also assumed because the process is seen in mammals as well as amphibians that this "Nodal activity" was evolutionarily conserved. However, if so, how did it get there in the first place?
We have previously reported on the complexity of embryological development. Upon fertilization, a process unfolds that is both highly complex and highly regulated. This process has all of the hallmarks of being directed to a particular end goal, which in turn is a hallmark of design. Now we know that the non-coding DNA, the so-called "junk DNA" portion of the genome, plays a key role in this process.
So you see how the study of development benefits from a scientific paradigm that allows for design. This study sheds light on cell fate, suggesting new approaches in research related to pluripotent stem cells.
The formation of the mesoderm, endoderm, and ectoderm is not a small accomplishment, and it is certainly not something that could have resulted from a stepwise process that builds from the parts to the whole. The system must already be in place for reproduction to occur, yet the ability to reproduce is the very driving force of natural selection. It's enough to cast a Darwinian evolutionary theorist into the depths of despair.