The Canonical Notch Signaling Pathway: Unfolding the Activation Mechanism

TRP channels are the vanguard of our sensory systems, responding to temperature, touch, pain, osmolarity, pheromones, taste and other stimuli. But their role is much broader than classical sensory transduction. They are an ancient sensory apparatus for the cell, not just the multicellular organism, and they have been adapted to respond to all manner of stimuli, from both within and outside the cell.

TRP channels as cellular sensors

Cell motility in viscous fluids is ubiquitous and affects many biological processes, including reproduction, infection and the marine life ecosystem. Here we review the biophysical and mechanical principles of locomotion at the small scales relevant to cell swimming, tens of micrometers and below. At this scale, inertia is unimportant and the Reynolds number is small. Our emphasis is on the simple physical picture and fundamental flow physics phenomena in this regime. We first give a brief overview of the mechanisms for swimming motility, and of the basic properties of flows at low Reynolds number, paying special attention to aspects most relevant for swimming such as resistance matrices for solid bodies, flow singularities and kinematic requirements for net translation. Then we review classical theoretical work on cell motility, in particular early calculations of swimming kinematics with prescribed stroke and the application of resistive force theory and slender-body theory to flagellar locomotion. After examining the physical means by which flagella are actuated, we outline areas of active research, including hydrodynamic interactions, biological locomotion in complex fluids, the design of small-scale artificial swimmers and the optimization of locomotion strategies. (Some figures in this article are in colour only in the electronic version) This article was invited by Christoph Schmidt.

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The hydrodynamics of swimming microorganisms

Mitochondrial morphology is determined by a dynamic equilibrium between organelle fusion and fission, but the significance of these processes in vertebrates is unknown. The mitofusins, Mfn1 and Mfn2, have been shown to affect mitochondrial morphology when overexpressed. We find that mice deficient in either Mfn1 or Mfn2 die in midgestation. However, whereas Mfn2 mutant embryos have a specific and severe disruption of the placental trophoblast giant cell layer, Mfn1-deficient giant cells are normal. Embryonic fibroblasts lacking Mfn1 or Mfn2 display distinct types of fragmented mitochondria, a phenotype we determine to be due to a severe reduction in mitochondrial fusion. Moreover, we find that Mfn1 and Mfn2 form homotypic and heterotypic complexes and show, by rescue of mutant cells, that the homotypic complexes are functional for fusion. We conclude that Mfn1 and Mfn2 have both redundant and distinct functions and act in three separate molecular complexes to promote mitochondrial fusion. Strikingly, a subset of mitochondria in mutant cells lose membrane potential. Therefore, mitochondrial fusion is essential for embryonic development, and by enabling cooperation between mitochondria, has protective effects on the mitochondrial population.

/pdf/mitofusins-mfn1-and-mfn2-coordinately-regulate-mitochondrial-34q0bqfnrp.pdf

Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development

https://www.cell.com/cell/pdf/S0092-8674(03)00111-9.pdf

The Molecular Motor Toolbox for Intracellular Transport

Randomization of Left–Right Asymmetry due to Loss of Nodal Cilia Generating Leftward Flow of Extraembryonic Fluid in Mice Lacking KIF3B Motor Protein

Substantial insight has recently been achieved into the mechanisms responsible for the generation of left–right (L–R) asymmetry in the vertebrate body plan1,2,3,4. However, the mechanism that underlies the initial breaking of symmetry has remained unclear. In the mouse, a leftward fluid flow on the ventral side of the node caused by the vortical motion of cilia (referred to as nodal flow) is implicated in symmetry breaking5, but direct evidence for the role of this flow has been lacking. Here we describe the development of a system in which mouse embryos are cultured under an artificial fluid flow and with which we have examined how flow affects L–R patterning. An artificial rightward flow that was sufficiently rapid to reverse the intrinsic leftward nodal flow resulted in reversal of situs in wild-type embryos. The artificial flow was also able to direct the situs of mutant mouse embryos with immotile cilia. These results provide the first direct evidence for the role of mechanical fluid flow in L–R patterning.

Determination of left–right patterning of the mouse embryo by artificial nodal flow

Targeted Disruption of Mouse Conventional Kinesin Heavy Chain kif5B, Results in Abnormal Perinuclear Clustering of Mitochondria

KIF3A is a classical member of the kinesin superfamily proteins (KIFs), ubiquitously expressed although predominantly in neural tissues, and which forms a heterotrimeric KIF3 complex with KIF3B or KIF3C and an associated protein, KAP3. To elucidate the function of the kif3A gene in vivo, we made kif3A knockout mice. kif3A −/− embryos displayed severe developmental abnormalities characterized by neural tube degeneration and mesodermal and caudal dysgenesis and died during the midgestational period at ∼10.5 dpc (days post coitum), possibly resulting from cardiovascular insufficiency. Whole mount in situ hybridization of Pax6 revealed a normal pattern while staining by sonic hedgehog ( shh ) and Brachyury ( T ) exhibited abnormal patterns in the anterior-posterior (A-P) direction at both mesencephalic and thoracic levels. These results suggest that KIF3A might be involved in mesodermal patterning and in turn neurogenesis.

/pdf/left-right-asymmetry-and-kinesin-superfamily-protein-kif3a-4jyaan25qx.pdf

Left-Right Asymmetry and Kinesin Superfamily Protein KIF3A: New Insights in Determination of Laterality and Mesoderm Induction by kif3A−/− Mice Analysis

https://www.cell.com/molecular-cell/pdf/S1097-2765(00)80197-5.pdf

Shigenori Nonaka

Papers

Randomization of Left–Right Asymmetry due to Loss of Nodal Cilia Generating Leftward Flow of Extraembryonic Fluid in Mice Lacking KIF3B Motor Protein

Determination of left–right patterning of the mouse embryo by artificial nodal flow

Targeted Disruption of Mouse Conventional Kinesin Heavy Chain kif5B, Results in Abnormal Perinuclear Clustering of Mitochondria

Left-Right Asymmetry and Kinesin Superfamily Protein KIF3A: New Insights in Determination of Laterality and Mesoderm Induction by kif3A−/− Mice Analysis

Abnormal Nodal Flow Precedes Situs Inversus in iv and inv mice