Browsing by Author "Goetz, Sarah C"

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    Elucidating the Role of TTBK2 in Cilia Stability
    (2022) Nguyen, Abraham Viet

    Cilia are hair-like structures found on a number of cells serving a variety of different functions. The common denominator between cilia is that they are made up of a microtubule-based projection called the axoneme and nucleated by a modified mother centriole termed the basal body. While there has been an extensive amount of work interrogating ciliogenesis, the requirements for cilia maintenance has less been appreciated. Recent work is also starting to reveal that the cilia biogenesis pathways for these different cilia are different, suggesting that the requirements for their maintenance may also be different.

    TTBK2 is a key regulator of primary cilia assembly. In the following study, we identify novel pathways that regulate and are regulated by TTBK2 using BioID. Using tamoxifen-inducible Cre-recombinase cell and mouse systems, we are able to allow these systems to build cilia, deplete TTBK2 levels after cilia formation by tamoxifen induction, assess changes to different types of cilia over time, and validate some of the protein interactions we identified by BioID.

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    Spinocerebellar ataxia type 11-associated alleles of Ttbk2 dominantly interfere with ciliogenesis and cilium stability.
    (PLoS genetics, 2018-12-10) Bowie, Emily; Norris, Ryan; Anderson, Kathryn V; Goetz, Sarah C
    Spinocerebellar ataxia type 11 (SCA11) is a rare, dominantly inherited human ataxia characterized by atrophy of Purkinje neurons in the cerebellum. SCA11 is caused by mutations in the gene encoding the Serine/Threonine kinase Tau tubulin kinase 2 (TTBK2) that result in premature truncations of the protein. We previously showed that TTBK2 is a key regulator of the assembly of primary cilia in vivo. However, the mechanisms by which the SCA11-associated mutations disrupt TTBK2 function, and whether they interfere with ciliogenesis were unknown. In this work, we present evidence that SCA11-associated mutations are dominant negative alleles and that the resulting truncated protein (TTBK2SCA11) interferes with the function of full length TTBK2 in mediating ciliogenesis. A Ttbk2 allelic series revealed that upon partial reduction of full length TTBK2 function, TTBK2SCA11 can interfere with the activity of the residual wild-type protein to decrease cilia number and interrupt cilia-dependent Sonic hedgehog (SHH) signaling. Our studies have also revealed new functions for TTBK2 after cilia initiation in the control of cilia length, trafficking of a subset of SHH pathway components, including Smoothened (SMO), and cilia stability. These studies provide a molecular foundation to understand the cellular and molecular pathogenesis of human SCA11, and help account for the link between ciliary dysfunction and neurodegenerative diseases.
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    TTBK2 and Primary Cilia are Required for Purkinje Cell Survival
    (2019) Bowie, Emily Josephine

    Primary cilia are a small microtubule based signaling organelle. Primary cilia can be found on almost every mammalian cell, including neurons and glia. Tau Tubulin Kinase 2 (TTBK2) is a critical regulator of the building of primary cilia, and mutations within Ttbk2 cause the adult-onset, neurodegenerative disease, Spinocerebellar Ataxia type 11 (SCA11). SCA11 is characterized by a loss of Purkinje neurons throughout the cerebellum causing ataxic phenotypes in affected individuals.

    Given this connection, this body of work aims to define the role of primary cilia in maintaining neuron homeostasis through further defining roles of Ttbk2 both in ciliary biology as well as it’s neuronal functions. Using various genetic mouse models, I have found new roles for Ttbk2 in cilium stability and function that may help explain in part the etiology of SCA11. I then go on to further characterize the roles for primary cilia in neurons using Ttbk2 genetic knockouts. I have found that primary cilia are essential for Purkinje cell survival and have characterized a new mouse model of SCA11.