Research Projects

There are more than 300 TMEM (TransMEMbrane) family protein-coding genes in humans. A number of these genes have been implicated in genetic and developmental disorders, highlighting their importance in development and human health. However, the in vivo role of these genes in the development of multicellular organisms is not well explored. In an RNAi screening targeting highly conserved TMEM protein-coding genes in fruit flies (Drosophila melanogaster), I discovered that the knockdown of a yet-uncharacterized gene, CG5861, affects development and potentially impairs Notch signaling. Interestingly, autosomal recessive mutations in its human ortholog, TMEM147, cause a genetic disorder with developmental delay, intellectual disabilities, and seizures- all of which could be caused by impaired Notch signaling. However, there is no study showing the importance of CG5861/TMEM147 in multicellular development and/or Notch signaling regulation. In this study, we will generate a humanized ‘fruit fly’ model and use it along with human cell line-based works to test how the loss of this gene affects development and Notch pathway. First, we will use CRISPR to generate a ‘humanized’ fly model and test the effects of patient-derived variants on development (Objective 1). Next, we will use cellular and biochemical tools and techniques to identify how the loss of this gene affects Notch signaling regulation (Objective 2). Finally, we will use human cell lines to validate the effects of Tmem147 loss on Notch signaling (Objective 3). Overall, our work will shed light on a novel function of Tmem147 in Notch signaling and development.