The alien mutation was previously identified in a mutagenesis screen (Herron et al., Nat Genetics 2002). Positional cloning revealed this to be a null mutation in the gene Ttc21b, which is required for protein transport within the primary cilium (Tran et al., Nat Genetics 2008). The alien mutant also has a severe brain patterning defect (Stottmann et al., Dev Biol, 2009). The role of Ttc21b in the developing forebrain and craniofacial tissues, and the role of cilia in development more broadly, is a major focus within the laboratory. One direction of this project is a tissue specific ablation of Ttc21b and other primary cilia genes in the in the developing forebrain and craniofacial tissues.
Evidence from human genetics studies suggest TTC21B is a node in a larger ciliary signaling network. We are studying how these genes interact through studies in the mouse and in vitro. We are also using a forward genetic approach to identify novel loci interacting with Ttc21b in mammalian development and disease. We have also used a Quantitative Trait Locus analysis to identify a gene we now believe at least partially explains the effects of genetic background on the alien forebrain mutation.
Work on this project is funded by the Cincinnati Children's Research Foundation, the March of Dimes Foundation and the NIH (NIGMS).
The alien forebrain has significant patterning defects at E18.5 (modified from Stottmann et al., Dev Biol 2009)
Emx1-Cre recombination pattern in the forebrain of the E13.5 embryo (eGFP Cre reporter).
Alien mutant embryos have craniofacial malformations.