The primary cilium has recently stepped into the spotlight, as a flood of data demonstrate 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 (Hh) signal transduction. Formation of cilia, in turn, is regulated by other signaling pathways, possibly including the planar cell polarity pathway. The cilium therefore represents a nexus for signaling pathways during development. The connections between cilia and developmental signaling have begun to clarify the basis of human diseases associated with ciliary dysfunction.
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.
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 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, 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. Hedgehog 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.
SummaryTbx5 and Tbx20 act synergistically to control vertebrate heart morphogenesis
Primary cilia are vital signaling organelles that extend from most types of cells, including neurons and glia. These structures are essential for development of many tissues and organs; however, their function in adult tissues, particularly neurons in the brain, remains largely unknown. Tau tubulin kinase 2 (TTBK2) is a critical regulator of ciliogenesis, and is also mutated in a hereditary neurodegenerative disorder, spinocerebellar ataxia type 11 (SCA11). Here, we show that conditional knockout of Ttbk2 in adult mice results in degenerative cerebellar phenotypes that recapitulate aspects of SCA11 including motor coordination deficits and defects to Purkinje cell (PC) integrity. We also find that the Ttbk2 conditional mutant mice quickly lose cilia throughout the brain. We show that conditional knockout of the key ciliary trafficking gene Ift88 in adult mice results in nearly identical cerebellar phenotypes to those of the Ttbk2 knockout, indicating that disruption of ciliary signaling is a key driver of these phenotypes. Our data suggest that primary cilia play an integral role in maintaining the function of PCs in the adult cerebellum and reveal novel insights into mechanisms involved in neurodegeneration.
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.
Despite the critical importance of TBX5 in normal development and disease, relatively little is known about the mechanisms by which TBX5 functions in the embryonic heart. Our present studies demonstrate that TBX5 is necessary to control the length of the embryonic cardiac cell cycle, with depletion of TBX5 leading to cardiac cell cycle arrest in late G 1 -or early S-phase. Blocking cell cycle progression by TBX5 depletion leads to a decrease in cardiac cell number, an alteration in the timing of the cardiac differentiation program, defects in cardiac sarcomere formation, and ultimately, to cardiac programmed cell death. In these studies we have also established that terminally differentiated cardiomyocytes retain the capacity to undergo cell division. We further show that TBX5 is sufficient to determine the length of the embryonic cardiac cell cycle and the timing of the cardiac differentiation program. Thus, these studies establish a role for TBX5 in regulating the progression of the cardiac cell cycle.
Background: Physicians are expected to effect patient care by giving orders to members of a healthcare team. Because women are socialized to be less directive than men, the assertive behavior required of new physicians may be experienced differently by male and female residents. We sought to explore the effects of gender and year of training on residents' experiences and perceived ability to direct patient care. Methods: This was a mixed-methods, cross-sectional, descriptive study employing a quantitative written survey and qualitative interviews among internal medicine residents at an academic health center. Measurements included questionnaires and interviews about stress, assertiveness, and personal factors that influence their effectiveness in directing patient care. Analyses examined differences by gender and year of training. Results: One hundred residents were invited to participate; 65 returned questionnaires, and 16 of these residents were interviewed. Compared with male residents, female residents selected less assertive behaviors for clinical scenarios (p ϭ 0.047) and were more likely to perceive gender as inhibiting their ability to influence patient care (p Ͻ 0.01). Stress associated with being assertive varied more with experience than gender. Interviews corroborated these findings and supported the complexity of gender norms for behavior for female residents in a directive leadership position. Conclusions: When compared with male peers, female residents reported more gender issues in residency and chose less assertive behaviors in clinical scenarios. Experience mitigated some gender differences. Our findings suggest that discussion of the existing research on prescriptive gender norms for behavior and leadership may be warranted in resident orientation.
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