Investigating Genetic Interactions Between the RNA Binding Protein dNab2 and Planar Cell Polarity (PCP) Components in Drosophila melanogaster Open Access
Lee, Wei-Hsuan (Spring 2019)
Abstract
Mutations in the ubiquitously expressed polyadenosine RNA binding protein (RBP) ZC3H14 are linked to a monogenic, non-syndromic autosomal recessive intellectual disability. ZC3H14 has a functionally conserved ortholog, dNab2, in Drosophila melanogaster. Previous research in the Moberg and Corbett Labs has shown that dNab2 is autonomously required within neurons to pattern axon projection in the mushroom body (MB). MB axons lacking dNab2 project aberrantly across the brain midline and show evidence of defective branching. Similarly, mutations in components of the well-conserved planar cell polarity (PCP) pathway, which controls the planar orientation of static and motile cells, also cause MB axon mis-projection. Previous research in the Moberg Lab also shows that flies lacking dNab2 display kink sensory bristles (Pak et al., 2011), which is similar to the randomized orientation of sensory bristles observed in PCP mutants (Seifert & Mlodzik 2007). To assess if dNab2 controls axon projection and sensory bristle orientation in conjunction with the PCP pathway, and to identify genes that interact with dNab2 in neurodevelopment and other cellular contexts, we utilized a dNab2 overexpression model as the basis of a modifier screen. A preliminary test in the Moberg lab suggested that an allele of the Wnt receptor frizzled (fz) could suppress a rough eye phenotype caused by dNab2 overexpression, which provided foundation and motivation for broader examination of PCP candidates. This approach found evidence that alleles of several PCP pathway components could dominantly rescue a rough-eye phenotype caused by excess dNab2. These PCP mutations could also rescue the near-lethal phenotype of a dNab2 null allele and partially rescue an associated kinked thoracic bristle phenotype. Surprisingly, the rescue of dNab2 rough-eye phenotype could be observed in progeny of PCP allele ‘carriers’ that did not inherit the allele, suggesting an indirect modification effect through the germline. In sum, these findings reveal a consistent pattern of genetic interactions between PCP components and the dNab2 RBP that seem to reflect complex regulatory interactions between PCP signaling and dNab2. Future experiments could focus on molecular mechanism(s) that underlie these effects in neurons and the germline.
Table of Contents
Chapter 1: Background………………………………............................................………….……1
Chapter 2: PCP Alleles Interact with A dNab2 Transgene In The Eye……………………....…..10
Chapter 3: Indirect Modification Interactions Between PCP and dNab2……….………….…..18
Chapter 4: Potential Mechanism of the Indirect dNab2-PCP Interactions...……………...…..21
Chapter 5: PCP Alleles Rescue Effects Of dNab2 Genomic Loss……………………...……….....24
Chapter 6: Conclusions and Future Directions………………………………………...…....……....28
References………………………………………………………………………………...…...............….36
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Investigating Genetic Interactions Between the RNA Binding Protein dNab2 and Planar Cell Polarity (PCP) Components in Drosophila melanogaster () | 2019-04-08 15:54:18 -0400 |
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