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.
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► Tau tubulin kinase 2 (Ttbk2) is essential for mouse Shh signaling and ciliogenesis ► TTBK2 recruits IFT proteins and removes CP110 from the mother centriole ► TTBK2 recruitment to the basal body correlates with the removal of CP110 ► Human TTBK2 mutations that cause SCA11 inhibit cilia formation in wild-type cells
TTBK2 acts at the distal end of the basal body, where it promotes recruitment of IFT proteins, which build the ciliary axoneme. Truncating mutations in human TTBK2 cause spinocerebellar ataxia type 11, and mutant TTBK2 inhibits ciliogenesis in wild-type cells.
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
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
conditional mutant mice quickly lose cilia throughout the brain. We show that conditional knockout of the key ciliary trafficking gene
in adult mice results in nearly identical cerebellar phenotypes to those of the
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.
Abstract
The Rosetta mission provided detailed observations of the growth of a cavity in the solar wind around comet 67P/Churyumov–Gerasimenko. As the comet approached the Sun, the plasma of cometary ...origin grew enough in density and size to present an obstacle to the solar wind. Our results demonstrate how the initial slight perturbations of the solar wind prefigure the formation of a solar wind cavity, with a particular interest placed on the discontinuity (solar wind cavity boundary) passing over the spacecraft. The slowing down and heating of the solar wind can be followed and understood in terms of single particle motion. We propose a simple geometric illustration that accounts for the observations, and shows how a cometary magnetosphere is seeded from the gradual steepening of an initially slight solar wind perturbation. A perspective is given concerning the difference between the diamagnetic cavity and the solar wind cavity.
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.
Although components of possible Parkinson's disease can be found in very early documents, the first clear medical description was written in 1817 by James Parkinson. In the mid-1800s, Jean-Martin ...Charcot was particularly influential in refining and expanding this early description and in disseminating information internationally about Parkinson's disease. He separated Parkinson's disease from multiple sclerosis and other disorders characterized by tremor, and he recognized cases that later would likely be classified among the Parkinsonism-plus syndromes. Early treatments of Parkinson's disease were based on empirical observation, and anticholinergic drugs were used as early as the nineteenth century. The discovery of dopaminergic deficits in Parkinson's disease and the synthetic pathway of dopamine led to the first human trials of levodopa. Further historically important anatomical, biochemical, and physiological studies identified additional pharmacological and neurosurgical targets for Parkinson's disease and allow modern clinicians to offer an array of therapies aimed at improving function in this still incurable disease.
We present a comprehensive statistical study of magnetic holes, defined as localized decreases of the magnetic field strength of at least 50%, in the solar wind near Mercury, using MESSENGER orbital ...data. We investigate the distributions of several properties of the magnetic holes, such as scale size, depth, and associated magnetic field rotation. We show that the distributions are very similar for linear magnetic holes (with a magnetic field rotation across the magnetic holes of less than 25°) and rotational holes (rotations >25°), except for magnetic holes with very large rotations (≳140°). Solar wind magnetic hole scale sizes follow a log‐normal distribution, which we discuss in terms of multiplicative growth. We also investigate the background magnetic field strength of the solar wind surrounding the magnetic holes, and conclude that it is lower than the average solar wind magnetic field strength. This is consistent with finding solar wind magnetic holes in high‐β regions, as expected if magnetic holes have a connection to magnetic mirror mode structures. We also present, for the first time, comprehensive statistics of isolated magnetic holes in a planetary magnetosheath. The properties of the magnetosheath magnetic holes are very similar to the solar wind counterparts, and we argue that the most likely interpretation is that the magnetosheath magnetic holes have a solar wind origin, rather than being generated locally in the magnetosheath.
Key Points
We present a comprehensive statistical study of magnetic holes in the near‐Mercury solar wind and magnetosheath
We find that magnetic hole scale sizes are log‐normally distributed
We suggest that a majority of the magnetosheath magnetic holes have a solar wind origin
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.
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