Unlocking first steps of organ and tissue development
New research uncovers the first steps of how human organs and tissues develop - unlocking new potential for diagnosing and understanding developmental disorders.
For the first time, the precise way individual human organs and tissue develop has been mapped — providing new insight into how genetic disorders can occur during the crucial early phase of development.
The research, carried out by a team from the University of Manchester and Central Manchester University Hospitals, NHS Foundation Trust, United Kingdom, is published in the current issue of the journal eLife.
Concentrating on the period know as organogenesis — beginning with neurulation in the the 3rd week and extending through the 8th week of pregnancy — points to which organs and tissue first develope from primitive precursor or unipotent cells. Precursor cells have lost most or all the multipotency of stem cells. They are blast cells with a capacity to differentiate into only one cell type.
This study helps explain how all genetic signals pull together into a body plan.
Starting with established knowledge that genes control how organs and tissues develop by downloading DNA code into RNA molecules — the team used RNA-sequencing to identify all the genetic messages at play in organ development.
Researchers developed a computational model decoding the complex patterns of gene activity across all tissues to understand the mechanisms by which human organ systems are built. The model correctly identified many genes known to cause developmental problems — such as 'hole in the heart' — and point to new genes in unsolved developmental disorders. Leading researchers to predict future improvements in gene diagnoses for patients with disorders.
"Until now, remarkably little has been known about human organogenesis — the assembly phase for organs and tissues. Errors at this stage can result in miscarriage or serious birth defects.
"Our research brings a new knowledge base, hopefully leading to clinicians being able to make new diagnoses and providing an early blueprint for scientists working with stem cells in the laboratory."
Neil Hanley, Professor of Medicine, The University of Manchester School of Medical Sciences, and lead author of the report.
In an exciting lead to the future, the authors also found a huge array of unexpected genetic activity. Over 6,000 new genetic messages were identified in the so-called non-coding RNA.
RNA that is not translated into a protein uses synonyms such as non-protein-coding RNA (npcRNA), non-messenger RNA (nmRNA), functional RNA (fRNA) or simply RNA. Epigenetic related ncRNAs include miRNA, siRNA, piRNA and lncRNA. In general, ncRNAs regulate gene expression at transcription and post-transcription levels.
The researchers now have the major challenge of trying to work out how these potential new players fit together in orchestrating how our body's organs and tissues are put together.
Human organogenesis is when severe developmental abnormalities commonly originate. However, understanding this critical embryonic phase has relied upon inference from patient phenotypes and assumptions from in vitro stem cell models and non-human vertebrates. We report an integrated transcriptomic atlas of human organogenesis. By lineage-guided principal components analysis, we uncover novel relatedness of particular developmental genes across different organs and tissues and identified unique transcriptional codes which correctly predicted the cause of many congenital disorders. By inference, our model pinpoints co-enriched genes as new causes of developmental disorders such as cleft palate and congenital heart disease. The data revealed more than 6000 novel transcripts, over 90% of which fulfil criteria as long non-coding RNAs correlated with the protein-coding genome over megabase distances. Taken together, we have uncovered cryptic transcriptional programs used by the human embryo and established a new resource for the molecular understanding of human organogenesis and its associated disorders.
Dave T Gerrard Andrew A Berry Rachel E Jennings Karen Piper Hanley Nicoletta Bobola Neil A Hanley
Paper: eLife, https://elifesciences.org/content/5/e15657
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Sep 7, 2016 Fetal Timeline Maternal Timeline News News Archive
Organogenesis, the organization of cells into individual tissues, occurs weeks 3 to 8,
with structural processes depicted as Carnegie Stages 1 through 23 — now detailed
as genetic outcomes by researchers at the University of Manchester and Central
Manchester University Hospitals, NHS Foundation Trust, United Kingdom.
Image Credit: The Visible Embryo and The University of Manchester
and Central Manchester University Hospitals, NHS Foundation Trust, UK