A rare and complex genetic disorder has provided Hopkins researchers with an unprecedented glimpse into how we sense temperature and texture. Writing in Proceedings of the National Academy of Sciences, the team, led by Nicholas Katsanis at the School of Medicine, identified the primary cilium, a feature of nearly all cells, as playing a critical role.
The disease in question is Bardet-Biedl syndrome (BBS), which is caused by an inherited genetic mutation. The complex nature of BBS has puzzled physicians and researchers since it was first described in 1866.
People with BBS manifest a broad range of symptoms, most of which involve a reduction or loss of sensation. Blindess and anosmia (loss of smell) are common, as are many seemingly unrelated features, such as obesity, mental retardation and kidney disease.
Recent research has focused on defects of non-motile cilia, organelles usually associated with sensory function. Non-motile cilia - as their name suggests - lack the locomotor abilities of motile cilia, such as those found in the trachea and lungs. Instead, they tend to be specialized for receiving a specific environmental stimulus.
For example, the outer segments of retinal photoreceptors - which contain light-absorbing pigments - are modified non-motile cilia, as are the aroma-detecting parts of the olfactory cells in the nose.
In BBS, mutations in two genes, Bbs1 and Bbs4, have been implicated in the malfunction of non-motile cilia. Normal copies of the two genes usually produce proteins found primarily in cilia.
While the link between genetic mutation and malfunction in vision, smell and hearing has been well-established, other sensory neurons exist whose cilia are not as visibly important to their function.
Most other cells in the body possess another kind of non-motile cilium called the primary cilium. Long thought to be useless evolutionary leftovers, primary cilia have only come into the spotlight within the last few years.
The finding in 2000 that cilia in kidney cells are critical to proper renal function sheds much light on both their structure and physiological function.
Building and maintaining a primary cilium was found to depend on a process called intraflagellar transport (IFT). (Flagellum is synonymous with cilium.) IFT allows cells to shuttle cargo up and down the inner length of the cilium, called the axoneme.
Usually, proteins necessary for ciliary growth and maintenance are shuttled toward the cilium's tip while extracellular signals are shuttled towards the cell body.
No evidence exists of the presence of primary cilia in the peripheral sensory neurons - located in the epidermis - that allow us to feel texture, temperature and pain.
Katsanis and his team used a technique in which they treated sensory neurons with a stain that specifically labels ciliary proteins; the results unequivocally confirmed the existence of primary cilia.
Next, the researchers engineered mice to possess the same genetic mutations as human cases of BBS. Behaviorally, the mutant mice were slower in withdrawing their tails from hot water, suggesting a defective thermosensory (that is, temperature-sensing) response. It also took a stronger pinch to get the mutants to react compared to normal mice.
Though the behavioral deficits of BBS-related genetic mutations were clear, Katsanis and his colleagues went further in describing their molecular basis.
Compared to those of normal mice, the researchers found fewer temperature and texture receptors in the sensory neurons of mutant mice, suggesting defects in the ways receptors are moved to the neurons' epidermal ends.
Thus it appears that the normal protein products of Bbs1 and Bbs4 are critical to IFT; consequently, it's likely that defective IFT is the root cause of many symptoms of BBS.
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