Sarah Goetz

Positions:

Assistant Professor of Pharmacology & Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Assistant Professor of Cell Biology

Cell Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Affiliate of the Regeneration Next Initiative

Regeneration Next Initiative
School of Medicine

Education:

B.A. 2001

Macalester College

Ph.D. 2007

University of North Carolina - Chapel Hill

Grants:

Characterizing the role of TTBK proteins in ciliogenesis and neural function

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Identifying the molecular networks regulating cilium assembly and signaling

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Identifying the molecular networks regulating cilium assembly and signaling

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Defining biochemical mechanisms of dominant interference by disease-causing variants of TTBK2

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

Spinocerebellar ataxia type 11-associated alleles of Ttbk2 dominantly interfere with ciliogenesis and cilium stability.

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.
Authors
Bowie, E; Norris, R; Anderson, KV; Goetz, SC
MLA Citation
Bowie, Emily, et al. “Spinocerebellar ataxia type 11-associated alleles of Ttbk2 dominantly interfere with ciliogenesis and cilium stability.Plos Genet, vol. 14, no. 12, Dec. 2018, p. e1007844. Pubmed, doi:10.1371/journal.pgen.1007844.
URI
https://scholars.duke.edu/individual/pub1364790
PMID
30532139
Source
pubmed
Published In
Plos Genet
Volume
14
Published Date
Start Page
e1007844
DOI
10.1371/journal.pgen.1007844

The Meckel syndrome- associated protein MKS1 functionally interacts with components of the BBSome and IFT complexes to mediate ciliary trafficking and hedgehog signaling.

The importance of primary cilia in human health is underscored by the link between ciliary dysfunction and a group of primarily recessive genetic disorders with overlapping clinical features, now known as ciliopathies. Many of the proteins encoded by ciliopathy-associated genes are components of a handful of multi-protein complexes important for the transport of cargo to the basal body and/or into the cilium. A key question is whether different complexes cooperate in cilia formation, and whether they participate in cilium assembly in conjunction with intraflagellar transport (IFT) proteins. To examine how ciliopathy protein complexes might function together, we have analyzed double mutants of an allele of the Meckel syndrome (MKS) complex protein MKS1 and the BBSome protein BBS4. We find that Mks1; Bbs4 double mutant mouse embryos exhibit exacerbated defects in Hedgehog (Hh) dependent patterning compared to either single mutant, and die by E14.5. Cells from double mutant embryos exhibit a defect in the trafficking of ARL13B, a ciliary membrane protein, resulting in disrupted ciliary structure and signaling. We also examined the relationship between the MKS complex and IFT proteins by analyzing double mutant between Mks1 and a hypomorphic allele of the IFTB component Ift172. Despite each single mutant surviving until around birth, Mks1; Ift172avc1 double mutants die at mid-gestation, and exhibit a dramatic failure of cilia formation. We also find that Mks1 interacts genetically with an allele of Dync2h1, the IFT retrograde motor. Thus, we have demonstrated that the MKS transition zone complex cooperates with the BBSome to mediate trafficking of specific trans-membrane receptors to the cilium. Moreover, the genetic interaction of Mks1 with components of IFT machinery suggests that the transition zone complex facilitates IFT to promote cilium assembly and structure.
Authors
Goetz, SC; Bangs, F; Barrington, CL; Katsanis, N; Anderson, KV
MLA Citation
Goetz, Sarah C., et al. “The Meckel syndrome- associated protein MKS1 functionally interacts with components of the BBSome and IFT complexes to mediate ciliary trafficking and hedgehog signaling.Plos One, vol. 12, no. 3, 2017, p. e0173399. Pubmed, doi:10.1371/journal.pone.0173399.
URI
https://scholars.duke.edu/individual/pub1241602
PMID
28291807
Source
pubmed
Published In
Plos One
Volume
12
Published Date
Start Page
e0173399
DOI
10.1371/journal.pone.0173399

The spinocerebellar ataxia-associated gene Tau tubulin kinase 2 controls the initiation of ciliogenesis.

The primary cilium has critical roles in human development and disease, but the mechanisms that regulate ciliogenesis are not understood. Here, we show that Tau tubulin kinase 2 (TTBK2) is a dedicated regulator of the initiation of ciliogenesis in vivo. We identified a null allele of mouse Ttbk2 based on loss of Sonic hedgehog activity, a signaling pathway that requires the primary cilium. Despite a normal basal body template, Ttbk2 mutants lack cilia. TTBK2 acts at the distal end of the basal body, where it promotes the removal of CP110, which caps the mother centriole, and promotes recruitment of IFT proteins, which build the ciliary axoneme. Dominant truncating mutations in human TTBK2 cause spinocerebellar ataxia type 11 (SCA11); these mutant proteins do not promote ciliogenesis and inhibit ciliogenesis in wild-type cells. We propose that cell-cycle regulators target TTBK2 to the basal body, where it modifies specific targets to initiate ciliogenesis.
Authors
Goetz, SC; Liem, KF; Anderson, KV
MLA Citation
Goetz, Sarah C., et al. “The spinocerebellar ataxia-associated gene Tau tubulin kinase 2 controls the initiation of ciliogenesis.Cell, vol. 151, no. 4, Nov. 2012, pp. 847–58. Pubmed, doi:10.1016/j.cell.2012.10.010.
URI
https://scholars.duke.edu/individual/pub1116744
PMID
23141541
Source
pubmed
Published In
Cell
Volume
151
Published Date
Start Page
847
End Page
858
DOI
10.1016/j.cell.2012.10.010

The primary cilium: a signalling centre during vertebrate development.

The primary cilium has recently stepped into the spotlight, as a flood of data show that this organelle has crucial roles in vertebrate development and human genetic diseases. Cilia are required for the response to developmental signals, and evidence is accumulating that the primary cilium is specialized for hedgehog signal transduction. The formation of cilia, in turn, is regulated by other signalling pathways, possibly including the planar cell polarity pathway. The cilium therefore represents a nexus for signalling pathways during development. The connections between cilia and developmental signalling have begun to clarify the basis of human diseases associated with ciliary dysfunction.
Authors
Goetz, SC; Anderson, KV
MLA Citation
Goetz, Sarah C., and Kathryn V. Anderson. “The primary cilium: a signalling centre during vertebrate development.Nat Rev Genet, vol. 11, no. 5, May 2010, pp. 331–44. Pubmed, doi:10.1038/nrg2774.
URI
https://scholars.duke.edu/individual/pub1116745
PMID
20395968
Source
pubmed
Published In
Nat Rev Genet
Volume
11
Published Date
Start Page
331
End Page
344
DOI
10.1038/nrg2774

The primary cilium as a Hedgehog signal transduction machine.

The Hedgehog (Hh) signal transduction pathway is essential for the development and patterning of numerous organ systems, and has important roles in a variety of human cancers. Genetic screens for mouse embryonic patterning mutants first showed a connection between mammalian Hh signaling and intraflagellar transport (IFT), a process required for construction of the primary cilium, a small cellular projection found on most vertebrate cells. Additional genetic and cell biological studies have provided very strong evidence that mammalian Hh signaling depends on the primary cilium. Here, we review the evidence that defines the integral roles that IFT proteins and cilia play in the regulation of the Hh signal transduction pathway in vertebrates. We discuss the mechanisms that control localization of Hh pathway proteins to the cilium, focusing on the transmembrane protein Smoothened (Smo), which moves into the cilium in response to Hh ligand. The phenotypes caused by loss of cilia-associated proteins are complex, which suggests that cilia and IFT play active roles in mediating Hh signaling rather than serving simply as a compartment in which pathway components are concentrated. Hh signaling in Drosophila does not depend on cilia, but there appear to be ancient links between cilia and components of the Hh pathway that may reveal how this fundamental difference between the Drosophila and mammalian Hh pathways arose in evolution.
Authors
Goetz, SC; Ocbina, PJR; Anderson, KV
MLA Citation
Goetz, Sarah C., et al. “The primary cilium as a Hedgehog signal transduction machine.Methods Cell Biol, vol. 94, 2009, pp. 199–222. Pubmed, doi:10.1016/S0091-679X(08)94010-3.
URI
https://scholars.duke.edu/individual/pub1116746
PMID
20362092
Source
pubmed
Published In
Methods in Cell Biology
Volume
94
Published Date
Start Page
199
End Page
222
DOI
10.1016/S0091-679X(08)94010-3