Bird insight into human ciliopathies

Kiliopathies are genetic disorders caused by deficiencies in the structure and function of the eyelashes, organelles based on microtubules present on the surface of almost every cell in the human body that play a crucial role in cell signaling. Kiliopathies present a wide range of often serious clinical symptoms, which often affect the head and face and lead to conditions such as cleft palate and micrognathia (an underdeveloped lower jaw that can impair feeding and breathing). Although we understand many of the genetic causes of human cyliopathies, they are only half the story: the question remains as to why, at the cellular level, defective cilia cause developmental craniofacial abnormalities. Researchers have now discovered that cyliopathic micrognathia in an animal model is the result of abnormal differentiation and reshaping of the skeleton. The work of Christian Bonatt Paese, Evan Brooks and others from Samantha Brugmann’s lab at Cincinnati Children’s Hospital Medical Center in the US was published in Development magazine.

The researchers used the avian ta2 mutant as a model for the oral-facial-digital syndrome subtype 14 (OFD14), a rare human cyliopathy characterized by micrognathia. They observed malformation of the mandible in the early stages of ta2 mutant development. These defects are associated with uncontrolled progression through the cell cycle and excessive proliferation in skeletal progenitor cells. Importantly, these progenitor cells failed to differentiate into mature osteoblasts (bone-secreting cells), and this failure of differentiation subsequently led to a decrease in bone deposition and thus micrognathia. Researchers have also identified excessive bone resorption, a procedure that typically contributes to the final size and shape of the mandible, as an additional causative factor in ta2 microtany. This paper informs our understanding of the etiology of human ciliopathic micrognathia.

“We have identified various cellular processes that have been damaged during the onset of cyliopathic micrognathia,” says Samantha Brugmann. “We know from previous work that these processes respond to treatment with pharmacological agents, and we are currently testing a number of these agents to determine if it is possible to” rescue “tsiliopathic micrognathia. The therapeutic implications are extremely real.”

“Currently, we are also trying to discover how different organ systems respond to cilia loss and which molecular and signaling pathways are affected, to continue to improve our understanding of how to combat treatment for patients,” says Christian Bonatto Paese.

The paper illustrates how developmental biology can shed light on devastating genetic disorders. Brugmann concludes, “The most important impact of this study for me is how useful basic science and the bird embryo can be in discovering the mechanisms for human disease.”

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