'Junk DNA' Drives Embryonic Development
Sanford-Burnham researchers discover that microRNAs play an important role in germ layer formationthe process that determines which cells become which organs during embryonic development
An embryo is an amazing thing.
From just one initial cell, an entire living,
breathing body emerges, full of working cells and organs.
It comes as no surprise that embryonic development
is a very carefully orchestrated processeverything
has to fall into the right place at the right time.
Developmental and cell biologists study this very thing,
unraveling the molecular cues that determine
how we become human.
"One of the first, and arguably most important, steps in development is the allocation of cells into three germ layersectoderm, mesoderm, and endodermthat give rise to all tissues and organs in the body," explains Mark Mercola, Ph.D., professor and director of Sanford-Burnham's Muscle Development and Regeneration Program in the Sanford Children's Health Research Center.
In a study published in the journal Genes & Development*, Mercola and his team, including postdoctoral researcher Alexandre Colas, Ph.D., and Wesley McKeithan, discovered that microRNAs play an important role in this cell- and germ layer-directing process during development.
MicroRNA: one man's junk is another's treasure
MicroRNAs are small pieces of genetic material
similar to the messenger RNA that carries protein
encoding recipes from a cell's genome out to the
protein-building machinery in the cytoplasm.
Only microRNAs don't encode proteins.
So, for many years, scientists dismissed
the regions of the genome that encode these
small, non-protein coding RNAs as "junk."
We now know that microRNAs are far from junk. They may not encode their own proteins, but they do bind messenger RNA, preventing their encoded proteins from being constructed. In this way, microRNAs play important roles in determining which proteins are produced (or not produced) at a given time.
MicroRNAs are increasingly recognized as an important part of both normal cellular function and the development of human disease.
So, why not embryonic development, too?
Directing cellular traffic
To pinpoint whichif anymicroRNAs influence germ layer formation in early embryonic development, Mercola and his team individually studied most (about 900) of the microRNAs from the human genome.
Researchers tested each microRNA's ability
to direct formation of mesoderm and endoderm
from embryonic stem cells. In doing so, they
discovered that two microRNA families
called let-7 and miR-18
block endoderm formation, while enhancing
mesoderm and ectoderm formation.
The researchers confirmed their finding by artificially blocking let-7 function and checking to see what happened. That move dramatically altered embryonic cell fate, diverting would-be mesoderm and ectoderm into endoderm and underscoring the microRNA's crucial role in development.
But they still wanted to know more…
How do let-7 and miR-18 work?
Mercola's team determined that these microRNAs
direct mesoderm and ectoderm formation by
dampening the TGFβ signaling pathway.
TGFβ is a molecule that influences many cellular
behaviors, including proliferation and differentiation.
When these microRNAs dampen TGF,
they affect the specific course of cell differentiation,
as some cells go on to become bone and others brain.
Mercola "We've now shown that microRNAs are powerful regulators of embryonic cell fate. But our study also demonstrates that screening techniques, combined with systems biology, provide a paradigm for whole-genome screening and its use in identifying molecular signals that control complex biological processes."
Whole-genome microRNA screening identifies let-7 and mir-18 as regulators of germ layer formation during early embryogenesis
Tight control over the segregation of endoderm, mesoderm, and ectoderm is essential for normal embryonic development of all species, yet how neighboring embryonic blastomeres can contribute to different germ layers has never been fully explained.
We postulated that microRNAs, which fine-tune many biological processes, might modulate the response of embryonic blastomeres to growth factors and other signals that govern germ layer fate. A systematic screen of a whole-genome microRNA library revealed that the let-7 and miR-18 families increase mesoderm at the expense of endoderm in mouse embryonic stem cells.
Both families are expressed in ectoderm and mesoderm, but not endoderm, as these tissues become distinct during mouse and frog embryogenesis. Blocking let-7 function in vivo dramatically affected cell fate, diverting presumptive mesoderm and ectoderm into endoderm.
siRNA knockdown of computationally predicted targets followed by mutational analyses revealed that let-7 and miR-18 down-regulate Acvr1b and Smad2, respectively, to attenuate Nodal responsiveness and bias blastomeres to ectoderm and mesoderm fates. These findings suggest a crucial role for the let-7 and miR-18 families in germ layer specification and reveal a remarkable conservation of function from amphibians to mammals.
This research was funded by the California Institute for Regenerative Medicine, the U.S. National Institutes of Health (National Heart, Lung, and Blood Institute grants R33 HL088266 and R01 HL113601), and the American Heart Association.
Colas AR, McKeithan WL, Cunningham TJ, Bushway PJ, Garmire LX, Duester G, Subramaniam S, & Mercola M (2012). Whole-genome microRNA screening identifies let-7 and mir-18 as regulators of germ layer formation during early embryogenesis. Genes & development PMID: 23152446
About Sanford-Burnham Medical Research Institute
Sanford-Burnham Medical Research Institute is dedicated to discovering the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. The Institute consistently ranks among the top five organizations worldwide for its scientific impact in the fields of biology and biochemistry (defined by citations per publication) and currently ranks third in the nation in NIH funding among all laboratory-based research institutes. Sanford-Burnham utilizes a unique, collaborative approach to medical research and has established major research programs in cancer, neurodegeneration, diabetes, and infectious, inflammatory, and childhood diseases. The Institute is especially known for its world-class capabilities in stem cell research and drug discovery technologies. Sanford-Burnham is a U.S.-based, non-profit public benefit corporation, with operations in San Diego (La Jolla), California and Orlando (Lake Nona), Florida. For more information, news, and events, please visit us at sanfordburnham.org.
Original article: http://beaker.sanfordburnham.org/2012/12/junk-dna-embryonic-development-microrna/