Finding human development's first gear
team has identified that 4 genes operate for only a few hours in the earliest stages of life, to perform as "first gear'" in the shift into a human embryo.
Genes formed 70 million years ago in an unstable area of human DNA. Today, Oxford University research has discovered that a very small set of genes actually play a key role initiating the early human.
Their study appears in BioMed Central.
In data published by the Human Genome Project in 2002, evolutionary biologist Professor Peter Holland and graduate student Anne Booth, identified and named the genes as (1) Argfx, (2) Leutx, (3) Dprx and (4) Tprx. They belong to the homeobox group of genes that are involved in the regulation of patterns for organ placement and limb development. They can also be called hox genes. These genes control the rate of transcription of gene information from DNA into messenger RNA via a specialized fold they have that binds to DNA. Other homeobox genes are known to direct the formation of tissues and organs. However, when researchers tried to find out exactly what (1) Argfx, (2) Leutx, (3) Dprx and (4) Tprx genes do, they had a problem.
"To find a gene's function, you first look to see where it is switched on — expressed. But wherever we looked for these genes we could not see them expressed, making their function more and more of a mystery — until researchers in China sequenced all the genes active in the very earliest stages of human development. That's when we found our genes switched on, and this gave us an important clue."
Peter Holland PhD, Department of Zoology, University of Oxford, United Kingdom
Researchers Dr Ignacio Maeso and Dr Thomas Dunwell, both from the Department of Zoology at University of Oxford, analysed the data carefully they discovered the genes are activated for an astonishingly brief period — when the embryo is a tiny ball of 8 to 16-cells. This stage marks the stage just before cells decide to become either part of the placenta or grow into the embryo itself. Then these genes are simply switched off.
"It was really shocking to find these genes are only read for a pulse of a few hours in our entire lifetime."
Ignacio Maeso PhD, Department of Zoology, University of Oxford and Centro Andaluz de Biología del Desarrollo, Consejo Superior de Investigaciones Científicas/Universidad Pablo de Olavide
To find out what they do, Dunwell examined the four genes by placing each in normal adult cells grown in culture. Peter Holland then commented: "If fertilization is the ignition key for human development, then these genes control the change into first gear."
There is also an evolutionary twist to the story. The team discovered that the genes are only found in placental mammals, those that carry their embryos internally, as we do.
"They are found on chromosome 19, known to be an unstable part of our genome. Think of it as a bubbling cauldron of DNA, with individual bits of DNA being added and taken away, occasionally forming whole new genes.
"At the dawn of placental mammals, 70 million years ago, these genes emerged and were grabbed by evolution to perform a new task, acting to control what cells do in the earliest stages of development."
Ignacio Maeso PhD
A central goal of evolutionary biology is to link genomic change to phenotypic evolution. The origin of new transcription factors is a special case of genomic evolution since it brings opportunities for novel regulatory interactions and potentially the emergence of new biological properties.
We demonstrate that a group of four homeobox gene families (Argfx, Leutx, Dprx, Tprx), plus a gene newly described here (Pargfx), arose by tandem gene duplication from the retinal-expressed Crx gene, followed by asymmetric sequence evolution. We show these genes arose as part of repeated gene gain and loss events on a dynamic chromosomal region in the stem lineage of placental mammals, on the forerunner of human chromosome 19. The human orthologues of these genes are expressed specifically in early embryo totipotent cells, peaking from 8-cell to morula, prior to cell fate restrictions; cow orthologues have similar expression. To examine biological roles, we used ectopic gene expression in cultured human cells followed by high-throughput RNA-seq and uncovered extensive transcriptional remodelling driven by three of the genes. Comparison to transcriptional profiles of early human embryos suggest roles in activating and repressing a set of developmentally-important genes that spike at 8-cell to morula, rather than a general role in genome activation.
We conclude that a dynamic chromosome region spawned a set of evolutionarily new homeobox genes, the ETCHbox genes, specifically in eutherian mammals. After these genes diverged from the parental Crx gene, we argue they were recruited for roles in the preimplantation embryo including activation of genes at the 8-cell stage and repression after morula. We propose these new homeobox gene roles permitted fine-tuning of cell fate decisions necessary for specification and function of embryonic and extra-embryonic tissues utilised in mammalian development and pregnancy.
Return to top of page
Jul 1, 2016 Fetal Timeline Maternal Timeline News News Archive
Hox genes are known to direct the formation of limbs and organs.
But these 4 are only active on the third day following fertilization.
Image Credit: The Visible Embryo