Cyclin D3 Activity Linked to Determination of Red Blood Cell Number and Size

Genome-wide association studies (GWAS) followed up by experiments on mouse and human red blood cells have revealed that the protein cyclin D3 is a critical element in the process that regulates red blood cell (RBC) number and size.

GWAS are necessarily broad in scope: that is they search the entire genome for associations rather than focusing on small candidate areas. These studies produce a tremendous amount of data, and the biological relevance of the GWAS results is often difficult to determine. However, in the current study, the experimental follow-up to the GWAS yielded concrete results.

Investigators at the Massachusetts Institute of Technology (Cambridge, USA) were seeking to define the molecular mechanism that controls number and size of red blood cells for any given individual. This information could then be applied to the prevention or treatment of anemia, which results from abnormalities in the RBC production process.

Results of the GWAS published in the August 28, 2012, online edition of the journal Genes and Development pinpointed the importance of the CCND3 gene, the gene that encodes cyclin D3. The investigators then genetically engineered a line of mice lacking CCND3. This Ccnd3 "knockout" mouse showed a dramatic increase in RBC size and a concomitant decrease in RCB number.

By examining human and mouse primary erythroid cells, the investigators demonstrated that the CCND3 gene product cyclin D3 regulated the number of cell divisions that erythroid precursors undergo during terminal differentiation, thereby controlling RBC size and number.

"This is one of the rare cases where we can explain a normal human-to-human variation," said senior author Dr. Harvey Lodish, professor of biology and bioengineering at the Massachusetts Institute of Technology. "In a sense, it is a window on human evolution. Why this should have happened, we have no idea, but it does."

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