Tmtc4 Interacts with C3G, Wntless, and Zfhx4: A Yeast Two-Hybrid Trap for Proteins Associated with Development of the Corpus Callosum
Popli, Tanav A.
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Agenesis of the corpus callosum (ACC) occurs when the corpus callosum, the large bundle of fibers that links the two hemispheres of the mammalian brain, fails to develop. This malformation is linked to over 50 congenital syndromes, including Temtamy Syndrome. This syndrome also presents with craniofacial abnormalities, ocular abnormalities, such as colobomata, or holes in the structures of the eyes, and mental retardation. Several researchers have identified and reported many slightly varying cases of Temtamy Syndrome. Studies of some of these cases have provided possible candidate genes which may play a role in the etiology of the disorder. Ankyrin repeat and MYND domain containing protein 1 (ANKMY1) was mutated in two cases of Temtamy Syndrome, while Transmembrane tetratricopeptide protein 4 (TMTC4) was found to span the breakpoint in a balanced translocation of a patient with isolated ACC. In this study, we performed a yeast two-hybrid protein trap on the products of these genes, indentifying five protein-coding sequences as partners for Ankmy1 and fourteen protein-coding sequences as interaction partners for Tmtc4. Of those sequences, none of the five Ankmy1 interactors had a known role in brain development, and only three of the proteins interacting with Tmtc4 have links to embryonic brain development. These three interacting proteins were Zfhx4, which regulates neural differentiation, Wntless, an important member of the Wnt family and integral to anteriorposterior axis formation and Wnt regulation in the brain, and C3G, a guanine exchange factor in the Ras signaling pathway which regulates neural precursor population and neuron migration in the cerebral cortex. Future work should confirm these interactions in mouse brain, as well as investigate the effects of the aberrant forms of the TMTC4 gene product observed in the affected individuals on these potential interactions, as they may play an important role in the etiology of ACC.