A gene called Six2 plays a critical role in the development of the kidney by keeping a population of 'parent' stem cells constantly available to produce the differentiated cells that give rise to specialized parts of the organ, according to investigators at St. Jude Children's Research Hospital. Differentiation is the process by which a progenitor (unspecialized) cell develops characteristics specific to its job in the body.
The kidney stem cells, called mesenchymal blastemal cells, are the source of cells triggered by chemical signals to differentiate into nephrons—the structures in the kidney that cleanse the blood of waste. The nephrons later become attached to ducts—tubes that collect the filtered blood as urine and direct it to the bladder. The St. Jude team showed that Six2 works by preventing some of the precursor cells from responding to these signals. This ensures there will be a continual source of undifferentiated stem cells available to maintain the growth of the kidney.
'Our work shows that Six2 is critical to preventing the developing kidney from running out of stem cells and collapsing into a mass of underdeveloped tissue,' said Guillermo Oliver, Ph.D., a member of the St. Jude Genetics and Tumor Cell Biology Department. Oliver is senior author of a report on this finding that appears in the online issue of The EMBO Journal.
'Our discovery of Six2's role in the developing kidney suggests that a similar mechanism exists in other developing organs,' said Michelle Self, the doctoral student in Oliver's laboratory who did most of the work on this project.
The St. Jude team showed that the kidneys in developing mice lacking the Six2 gene were remarkably smaller than normal mice and were non-functional at birth. In addition, they produced an abnormal excess in the number of nephrons that in turn produced a useless mass of tissue. Furthermore, the remaining precursor cells underwent apoptosis (cell suicide), further depleting the population of stem cells that could give rise to differentiated cells needed to form the kidney.
The researchers also found that Six2 works by suppressing a cascade of genetic interactions normally triggered by a gene called Wnt4, which usually drives the normal development of kidneys.