Forward genetics uncovers Tmem107, a novel regulator of embryonic patterning and ciliogenesis

In recent years, an understanding of the mechanisms underlying ciliogenesis and transport into cilia has begun to unfold. However, the full complement of proteins required for these processes and how they function is largely unknown. Through forward genetics, I isolated a mutant allele ( schlei) of mouse Transmembrane protein 107 (Tmem107), which plays multiple roles in ciliogenesis. Tmem107 mutants display reduced numbers of cilia, and those that form show multiple defects including bulbous tips and abnormally elongated, curled, or thin morphology. I demonstrate that Tmem107 is required for normal Sonic hedgehog (Shh) signaling in the mouse neural tube and limb, and acts in combination with the Gli transcription factors to pattern those tissues. I further show that Tmem107 is critical for the localization of several crucial ciliary membrane-associated proteins. These findings indicate that Tmem107 is a key factor responsible for determining the protein composition of the cilium. Furthermore, my investigation of a null allele for Tmem107 suggests that failure of this molecular role may underlie a variety of morphological defects, including cardiac abnormalities. Finally, preliminary results indicate that Tmem107 may be found at a variety of subcellular locations from the cis-Golgi to the cilium itself, suggesting that I have potentially discovered a new player that functions early in the process of ciliogenesis. Together, the characterization of Tmem107 mutants and establishment of a key role for Tmem107 in cilia composition represent a novel contribution toward the study of proteins required for ciliogenesis, Sonic hedgehog signaling, and embryogenesis.