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Lunenfeld scientists uncover a key secret to human development



By Dr. Greg Findlay

With over 200 different types of specialized cells and tissues in our bodies, why do we have a relatively similar number of genes as single-celled yeasts? New insight to this long-standing conundrum has been gained by scientists at Mount Sinai’s Samuel Lunenfeld Research Institute.

Recent work from Dr. Tony Pawson and his team at the Lunenfeld suggests that the proteins produced by these genes are far more complex in humans, an observation that also explains why human embryos have the ability to form tissues and organs at exactly the right stage of development. These findings not only have profound implications for our understanding of congenital birth defects and developmental disorders, they may also shed light onto how certain types of cancer may emerge.

In a fundamental study published recently in the leading journal Cell, Dr. Pawson’s team found that certain parts of the protein structure, called domains, work together to ensure that embryos develop in an orderly manner. “We wanted to understand how it is that every embryo develops into a child and then adult, in the same, orderly fashion,” says Dr. Greg Findlay, a post-doctoral researcher in Dr. Pawson’s lab. “Basically, what are the quality control steps being taken so that everything happens as it should?”

All cells, whether they be in yeast or in a human embryo, are exposed to external signals, which are sensed by various proteins on their surface that have multiple domains. In yeast, different domains tend to be on separate proteins, but in humans they are generally linked together, allowing a single protein to simultaneously interpret many signals, effectively a “molecular code” that allows for more complex responses.

The researchers found that a signaling protein called Sos1/Grb2 interprets a specific molecular code that instructs embryonic cells to form an essential tissue called primitive endoderm, which is one of the three primary cell types in the very early embryo. The protein domains of Sos1/Grb2 are fine-tuned to interpret the molecular code such that the primitive endoderm forms at exactly the right time during development.

“This new study explains why the domains of proteins, rather than the number of overall genes, increased dramatically during evolution. By using more domains to interpret an increasingly complex molecular code, key proteins that regulate development can effectively guarantee that tissues and organs are generated at the correct time and in the correct location in the embryo,” says Dr. Pawson.

Funded by the Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute and the Ontario Research Fund, this fundamental study deepens our understanding about human development, and how developmental process may go awry in congenital diseases and cancer.



sos1-grb2 protein.png

The image depicts a laboratory model of mammalian development. Embryonic stem cells are formed from very early stage embryos, and initially have the capacity to specialize into many adult cell types (Red cells, stained for the marker protein “Nanog”, top).

When the appropriate embryonic signals are received, the Sos1/Grb2 protein gives the green light for cells to initiate specialization of primitive endoderm, one of the very earliest tissues formed during mammalian development (Blue cells, stained for the marker protein “Dnmt3b”, bottom).

In doing so, the Sos1/Grb2 protein ensures that primitive endoderm specialization occurs at the correct stage during embryogenesis, which provides us with our first insights into how signaling proteins set developmental timing.




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