The nphp-2 and arl-13 genetic modules interact to regulate ciliogenesis and ciliary microtubule patterning in C. elegans.

Cilia are microtubule-based cellular organelles that mediate signal transduction. Cilia are organized into several structurally and functionally distinct compartments: the basal body, the transition zone (TZ), and the cilia shaft. In vertebrates, the cystoprotein Inversin localizes to a portion of the cilia shaft adjacent to the TZ, a region termed the "Inversin compartment" (InvC). The mechanisms that establish and maintain the InvC are unknown. In the roundworm C. elegans, the cilia shafts of amphid channel and phasmid sensory cilia are subdivided into two regions defined by different microtubule ultrastructure: a proximal doublet-based region adjacent to the TZ, and a distal singlet-based region. It has been suggested that C. elegans cilia also possess an InvC, similarly to mammalian primary cilia. Here we explored the biogenesis, structure, and composition of the C. elegans ciliary doublet region and InvC. We show that the InvC is conserved and distinct from the doublet region. nphp-2 (the C. elegans Inversin homolog) and the doublet region genes arl-13, klp-11, and unc-119 are redundantly required for ciliogenesis. InvC and doublet region genes can be sorted into two modules-nphp-2+klp-11 and arl-13+unc-119-which are both antagonized by the hdac-6 deacetylase. The genes of this network modulate the sizes of the NPHP-2 InvC and ARL-13 doublet region. Glutamylation, a tubulin post-translational modification, is not required for ciliary targeting of InvC and doublet region components; rather, glutamylation is modulated by nphp-2, arl-13, and unc-119. The ciliary targeting and restricted localization of NPHP-2, ARL-13, and UNC-119 does not require TZ-, doublet region, and InvC-associated genes. NPHP-2 does require its calcium binding EF hand domain for targeting to the InvC. We conclude that the C. elegans InvC is distinct from the doublet region, and that components in these two regions interact to regulate ciliogenesis via cilia placement, ciliary microtubule ultrastructure, and protein localization.

Ciliogenesis in Caenorhabditis elegans requires genetic interactions between ciliary middle segment localized NPHP-2 (inversin) and transition zone-associated proteins.

The cystic kidney diseases nephronophthisis (NPHP), Meckel-Gruber syndrome (MKS) and Joubert syndrome (JBTS) share an underlying etiology of dysfunctional cilia. Patients diagnosed with NPHP type II have mutations in the gene INVS (also known as NPHP2), which encodes inversin, a cilia localizing protein. Here, we show that the C. elegans inversin ortholog, NPHP-2, localizes to the middle segment of sensory cilia and that nphp-2 is partially redundant with nphp-1 and nphp-4 (orthologs of human NPHP1 and NPHP4, respectively) for cilia placement within the head and tail sensilla. nphp-2 also genetically interacts with MKS ciliopathy gene orthologs, including mks-1, mks-3, mks-6, mksr-1 and mksr-2, in a sensilla-dependent manner to control cilia formation and placement. However, nphp-2 is not required for correct localization of the NPHP- and MKS-encoded ciliary transition zone proteins or for intraflagellar transport (IFT). We conclude that INVS/NPHP2 is conserved in C. elegans and that nphp-2 plays an important role in C. elegans cilia by acting as a modifier of the NPHP and MKS pathways to control cilia formation and development.

Rate of force development and the lateralized readiness potential.

We examined the relationship between force and rate of force development aspects of movement dynamics and electroencephalogram motor components as reflected in the lateralized readiness potential (LRP). Using self-paced tasks, in Studies 1 and 3 we investigated whether differential speed and accuracy constraints in discrete and repetitive finger force production tasks influenced the LRP. These studies showed that speed tasks produced larger LRP than accuracy tasks regardless of whether the movement type was discrete or repetitive. In Studies 2 and 4 we studied four conditions with two levels of force and two levels of rate of force development. The largest LRPs were found with the greatest rate of force development. Overall, the four studies demonstrated that preparation for differential rates of force development is a major component reflected in the LRP.

Movement-related potentials are task or end-effector dependent: evidence from a multifinger experiment.

In a number of recent studies, the specific sensitivity of movement-related EEG potentials toward experimental manipulations of motor tasks using the index finger as a primary end-effector is well documented. The major question in this study was whether different movement-related EEG components are primarily end-effector or task dependent. Accordingly, the experimental task (i.e., the rate of force development - a ratio of peak force to time-to-peak force) was systematically manipulated and the effects of this manipulation on movement-related potentials were examined while subjects used either the index, middle, ring or little finger. Significant effects observed in this study were due mainly to the sensitivity of movement-related potentials preceding movement onset (Bereit shafts potential and motor potential) toward the specific finger performing the task and the sensitivity of components accompanying the task (movement-monitoring potential) toward the rate of force development. In addition, both movement-related potentials preceding and accompanying movement significantly changed as a function of the finger performing the slow task (lower rate of force development) with maximum values observed for the ring finger and minimal values observed for the index finger. Behaviorally subjects were less accurate during slow tasks regardless of the finger performing the task. In contrast, the amplitude of neither early nor late components of movement-related potentials changed as a function of the finger performing the fast task (higher rate of force development). Overall, our results are consistent with the notion that the whole complex of movement-related EEG potentials reflect a combination of factors including the selection of corresponding general motor programs as reflected in the amplitude of potentials preceding movement and specific elements of the task including rate of force development as reflected in the amplitude of potentials accompanying movement execution.

Movement-related potentials accompanying unilateral finger movements with special reference to rate of force development.

The aim of this study was to examine the relationship between force and rate of force development with electroencephalogram correlates. The primary question was whether the different components of movement related potentials (MRPs) were related to specific properties of force output while subjects performed index finger force production tasks. The peak force and rate of force development (e.g., a product of peak force over time-to-peak force) were manipulated, and the effects of these manipulations on components of MRPs preceding and accompanying force production tasks were examined. The hypothesis was that the rate of force development, rather than level of force itself, would directly influence the later component of MRPs. Consistent with this hypothesis was the finding that the amplitudes of MRP components preceding (MP) and accompanying (MMP, MTP) finger force production movements were significantly correlated with force development rate.