Primary cilia are ubiquitous organelles that receive and transduce molecular signals from the cell's molecular environment. Kif3a is an intraflagellar transport protein necessary for the extension and function of primary cilia. Conditional loss of Kif3a in cranial neural crest cells results in severe midfacial expansion and the loss of a tongue (aglossia). These phenotypes, along with our preliminary data, suggest that loss of Kif3a causes aberrant Sonic hedgehog (Shh) activity. Our objective is to determine how loss of Kif3a in neural crest cells affects Shh signaling within the craniofacial complex. In our first aim we will test the hypothesis that loss of Kif3a prevents the formation of the Gli3 repressor in neural crest cells of the developing midface. We will examine the role Kif3a plays in Gli3 processing and test if reintroduction of Gli3 repressor can rescue the midfacial phenotype. In our second aim we test if loss of Kif3a in neural crest cells disrupts Shh dependent signaling centers in neuroectoderm and facial ectoderm that are necessary for development and growth of the midface.
This aim tests the hypothesis that the midfacial phenotype in Kif3a mutants is caused by a secondary, non-cell autonomous mechanism. In our third aim we test the hypothesis that loss of Kif3a prevents formation of Gli activator in the developing tongue and lower jaw. Loss of the activator subsequently leads to a loss-of-Shh function. We will compare the molecular mechanism of aglossia between Kif3a conditional knock-outs and another, Shh-dependent aglossia model. Finally, we will determine the fate of mesodermally derived muscle precursor cells of the tongue in Kif3a mutants. Taken together, these studies will lend essential insight into the mechanism of primary cilia function in processing a Shh signal within the developing craniofacial complex. We expect our studies will provide novel insight into the etiology of craniofacial ciliopathies.

Public Health Relevance

Primary cilia are organelles that cells use to sense the molecular environment. Loss of cilia cause ciliopathies, a large disease class that affects multiple organs systems. This proposal studies the molecular basis of a ciliopathy that severely affects facial development.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Skeletal Biology Development and Disease Study Section (SBDD)
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Scholnick, Steven
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Cincinnati Children's Hospital Medical Center
United States
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Elliott, Kelsey H; Brugmann, Samantha A (2018) Sending mixed signals: Cilia-dependent signaling during development and disease. Dev Biol :
Elliott, Kelsey H; Millington, Grethel; Brugmann, Samantha A (2018) A novel role for cilia-dependent sonic hedgehog signaling during submandibular gland development. Dev Dyn 247:818-831
Metzler, Melissa A; Raja, Swetha; Elliott, Kelsey H et al. (2018) RDH10-mediated retinol metabolism and RAR?-mediated retinoic acid signaling are required for submandibular salivary gland initiation. Development 145:
Millington, Grethel; Elliott, Kelsey H; Chang, Ya-Ting et al. (2017) Cilia-dependent GLI processing in neural crest cells is required for tongue development. Dev Biol 424:124-137
Schock, Elizabeth N; Brugmann, Samantha A (2017) Neural crest cells utilize primary cilia to regulate ventral forebrain morphogenesis via Hedgehog-dependent regulation of oriented cell division. Dev Biol 431:168-178