Cilia and Hedgehog Signaling

Primary cilia are microtubule-based organelles that extend from the surface of most vertebrate cells (Fig. 1). Our genetic studies revealed that Hedgehog signaling in mammals depends on this organelle. Because aberrant Hedgehog signaling causes human tumors and because there is a large set of human inherited syndromes (the ciliopathies) that disrupt primary cilia, we study the mechanisms that link Hedgehog signaling to the primary cilium and that control cilia formation.

Changes in cilia structure in different ways have distinct effects on Hedgehog signaling.  For example, KIF7 is an evolutionarily conserved component of the Hh signaling pathway that is required to relay signals from the membrane protein Smoothened (Smo) to the transcription factors of the Ci/Gli family, and mouse Kif7 mutants show a mild expansion of Hh-dependent cell types in the neural tube (Fig. 1A). Mouse Kif7 mutants also make long, abnormal cilia (Fig. 1B). We showed that purified KIF7 protein binds directly to the plus-ends of growing microtubules, where it controls microtubule dynamics. In vivo, KIF7 localizes to cilia tips, where it organizes a compartment where Gli activation can be correctly regulated by Hh ligand (He et al., 2014).

Fig. 1.  (A). Kif7 mutations cause expansion of Sonic hedgehog-dependent ventral cell types in the neural tube (red = Shh expression; green marks the domain of motor neurons).  (B) Kif7 mutations lead to formation of long, abnormal primary cilia on neural progenitors

The lab is currently interested in defining the signals that control whether or not cells in the animal make cilia. For example, we identified Tau Tubulin Kinase 2 (TTBK2) as an essential regulator of the initiation of ciliogenesis (Goetz et al., 2012). To study the control of cilia formation, we generated double transgenic animals in which cilia are marked with a red fluorescent protein and the basal bodies that template cilia are marked with green fluorescent protein. These studies have led us to discover that ciliogenesis is regulated by lineage-specific mechanisms that are recapitulated in stem cells derived from specific embryonic lineages (Bangs et al., 2015).

We continue to identify and characterize new mutations that affect neural patterning and ciliogenesis.

 

Bangs, F. K, Schrode, N, Hadjantonakis, A-K. and Anderson, K. V.  Lineage Specificity of primary cilia in the mouse embryo.  Nature Cell Biology, Nature Cell Biology, Feb;17(2):113-22.

Bazzi, H. and Anderson, K. V. (2014) Acentriolar mitosis activates a p53-dependent apoptosis pathway in the mouse embryo. Proc Natl Acad Sci USA, 111: E1491-500.

He, M., Subramanian, R., Bangs, F., Omelchenko, T., Liem, K. F., Kapoor, T. M. and Anderson, K. V. (2014) The kinesin-4 protein KIF7 regulates mammalian Hedgehog signaling by organizing the cilia tip compartment. Nat Cell Biol 16: 663-672.

Insolera R, Bazzi H, Shao W, Anderson KV, Shi SH. (2014) Cortical neurogenesis in the absence of centrioles. Nat Neurosci. 17: 1528-35.

Goetz, S. C., Liem Jr., K. F. and Anderson, K. V. (2012) The Spinocerebellar Ataxia-associated Gene Tau Tubulin Kinase 2 (TTBK2) Controls the Initiation of Ciliogenesis. Cell 151: 847-858.

Tuson, M., He, M. and Anderson, K. V. (2011) Protein kinase A acts at the basal body of the primary cilium to prevent Gli2 activation and ventralization of the mouse neural tube. Development 138:4 921-4930.

Goetz, S. C., Anderson, K. V. (2010). The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet.11: 331-344.

Liem, K. F. Jr, He. M., Ocbina, P. J. and Anderson, K. V. (2009) Mouse Kif7/Costal2 is a cilia-associated protein that regulates Sonic hedgehog signaling. Proc Natl Acad Sci USA. 106: 13377-13382.

Weatherbee, S. D., Niswander, L. A. and Anderson, K. V. (2009) A mouse model for Meckel syndrome reveals Mks1 is required for ciliogenesis and Hedgehog signaling. Hum. Mol. Genet. 18: 4565-4575.

Caspary, T., Larkins, C. E. and Anderson, K. V. (2007) The graded response to Sonic Hedgehog depends on cilia architecture.  Dev. Cell, 12: 767-778.

Huangfu, D., Liu, A., Rakeman, A.S., Murcia, M.S., Niswander, L., Anderson, K.V. (2003) Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature. 426: 83-87.