From polycystic kidney disease (PKD) and retinal degenerative disease to planar cell polarity and Bardet-Biedl syndrome, these major human genetic diseases and syndromes all have one thing in common: cilia malfunctions. Dartmouth biology professor Roger Sloboda, whose own research delves deeply into the microscopic world of cilia, recently reviewed the current research available on these important structures and sought to piece together a big picture of how intraflagellar transport (IFT) works in the functioning of cilia and flagella. The article was published in Current Biology.

Intraflagellar transport (IFT) is crucial for the assembly and function of cilia and flagella, cell projections that have identical 9+2 microtubule arrangements. Much research energy has been channeled to answering how intraflagellar transport and the size of the trains are involved in flagellar and ciliary length control.

It was first demonstrated four decades ago that the flagella of Chlamydomonas, a biflagellate green alga, can be regenerated within an hour after removal. The process involved IFT transporting complexes called trains where cargo molecules of flagellar components like dynein arms and radial spokes are transported to site of assembly at the flagella tip and where retrograde cargo molecules are brought back to cell body where trains are reloaded.

“An understanding of what is going on often relies on figuring out what happens in mutant cells,” said Sloboda in an interview with DUJS. That is precisely how researchers were able to conclude that IFT functions in flagellar length control, i.e. they discovered that defects in or loss of any part of IFT machinery results in short or missing flagella.

A team of researchers including Marshall sought to explain the role of IFT in flagellar length control, formulating the balance-point model, which indicated that flagellar length is determined by a balance between the disassembly rate and assembly rate. According to the model, Marshall and coworkers proposed that a flagellum, be it short or long, contains the same number of IFT trains and thus, as the flagellum elongates, the trains carrying flagellar components arrive at the tip less frequently and the rate of elongation slows.

However, using video-enhanced DIC microscope, other researchers like Dentler disagreed, reporting that the number of IFT trains was not fixed but rather varied with flagellar length. A potential resolution of this contradiction lies in the fact that video-enhanced DIC is not well suited to detect size differences among trains and may have failed to detect small trains.

Further, researcher Engel showed that there is length variation in the size of the trains, i.e. trains in short flagella are larger and can thus carry more cargo than those in long flagella, “just as a trailer truck can carry more cargo than a pickup truck.” Another more recent group of researchers including Pigino reported that Chlamydomonas flagella contain two classes of IFT trains on the basis of size and morphology and concluded that one class comprises of anterograde IFT trains and the other comprises retrograde IFT trains. The puzzle pieces are slowly coming together.

“One key point to better understanding all this regulation to the growing flagellar tip lies with the issue of cargo loading onto the IFT trains. Does each train carry the same amount of cargo? Do large trains carry more cargo than short trains? There is still a lot we do not know,” said Sloboda.