The E3 ubiquitin ligase Mycbp2 genetically interacts with Robo2 to modulate axon guidance in the mouse olfactory system.

The E3 ubiquitin ligase Mycbp2 and it homologues play an important role in axon guidance and synaptogenesis in Drosophila, Caenorhabditis elegans, zebrafish and mouse. Despite this conserved function, the molecular and cellular basis of Mycbp2-dependent axon guidance remains largely unclear. We have examined here the effect of the loss-of-MYCBP2 function on the topography of the olfactory sensory neuron projection from the nasal cavity to the olfactory bulb in mice. A subpopulation of olfactory sensory axons failed to project to the dorsal surface of the olfactory bulb causing abnormal topography in this neural pathway. These defects were similar to the olfactory bulb phenotype in loss-of-ROBO2 function mice. While mice heterozygous for either Mycbp2 or Robo2 were normal, mice double heterozygous for these two genes produced severe defects in the olfactory system. Therefore, Mycbp2 and Robo2 were found to cooperate within a genetic network that has profound effects on axon guidance. The Mycbp2 phenotype could be partly explained by aberrant patterning of olfactory sensory neurons residing in the dorsal compartment of the nasal cavity. Some of these neurons fail to appropriately express Robo2 which is consistent with their aberrant projection to the ventral olfactory bulb. These results provide the first evidence linking an ubiquitin ligase to an axon guidance receptor during pathfinding in the developing mammalian nervous system.

Bilateral temporomandibular joint dislocation following pulmonary function testing: a case report and review of closed reduction techniques.

Temporomandibular joint dislocation is not a common presentation to the emergency department but it is one that requires prompt diagnosis and reduction. This is thought to be the first reported case of spontaneous bilateral temporomandibular joint dislocation after routine pulmonary function testing. The management of the case is discussed and a review of closed reduction techniques commonly used in the emergency department is presented.

Bilateral temporomandibular joint dislocation following pulmonary function testing: a case report and review of closed reduction techniques.

Temporomandibular joint (TMJ) dislocation is not a common presentation to the emergency department (ED) but one that requires prompt diagnosis and reduction. This is the first reported case of spontaneous bilateral TMJ dislocation after routine pulmonary function testing. The management of the case is discussed and a review of closed reduction techniques commonly used in the ED is presented.

Robo-Slit interactions regulate longitudinal axon pathfinding in the embryonic vertebrate brain.

The early network of axons in the embryonic brain provides connectivity between functionally distinct regions of the nervous system. While many of the molecular interactions driving commissural pathway formation have been deciphered, the mechanisms underlying the development of longitudinal tracts remain unclear. We have identified here a role for the Roundabout (Robo) family of axon guidance receptors in the positioning of longitudinally projecting axons along the dorsoventral axis in the embryonic zebrafish forebrain. Using a loss-of-function approach, we established that Robo family members exhibit complementary functions in the tract of the postoptic commissure (TPOC), the major longitudinal tract in the forebrain. Robo2 acted initially to split the TPOC into discrete fascicles upon entering a broad domain of Slit1a expression in the ventrocaudal diencephalon. In contrast, Robo1 and Robo3 restricted the extent of defasciculation of the TPOC. In this way, the complementary roles of Robo family members balance levels of fasciculation and defasciculation along this trajectory. These results demonstrate a key role for Robo-Slit signaling in vertebrate longitudinal axon guidance and highlight the importance of context-specific guidance cues during navigation within complex pathways.

Neuronal activity-related coupling in cortical arterioles: involvement of astrocyte-derived factors.

Neuronal activity-evoked dilatation was investigated in cortical arterioles in brain slices from mature rats maintained in vitro at 31-33 degrees C. In the presence of the thromboxane A2 agonist U46619 (75 nM) to preconstrict vessels, internal diameter decreased by 14.2% and rhythmic contractile activity (vasomotion) developed. Addition of the epoxygenase inhibitor miconazole (20 microm) produced a further decrease in diameter and increase in the frequency of vasomotion, suggesting that tonic release of epoxygenase products maintains a level of cerebrovascular dilator tone. Addition of 1 mum AMPA for 5 min evoked a 15.4 +/- 3.7% increase in diameter and the frequency of vasomotion decreased by -6.7 +/- 1.4 contractions min(-1). The response persisted in the presence of 1 mum TTX, indicating that it was independent of neuronal activity and thus likely to have been evoked by activation of AMPA receptors on astrocytes rather than neurones. The response to the brief (5 min) application of AMPA remained unchanged in the presence of miconazole (20 microm). Prolonged (30 min) application of AMPA produced a +12.1 +/- 1.5% increase in internal diameter and reduction in vasomotion (-8.4 +/- 1.7 contractions min(-1)) that were sustained throughout the stimulation period. However, when AMPA was applied in the presence of miconazole (20 microm) it evoked only a transient increase in diameter (+9.8 +/- 3.1%) and decrease in vasomotion (-6.6 +/- 1.5 contractions min(-1)) that lasted for less than 10 min despite continued application of AMPA. The results suggest that products of epoxygenase activity, probably epoxyeicosatrienoic acids (EETs) are involved in activity-related dilatation in cortical arterioles. Whilst epoxygenase activity is not required to initiate dilatation, it appears to be involved in sustaining the response. Thus EETs released from membrane stores could contribute to the initial stages, but once these have been depleted de novo synthesis of EETs is required to maintain the effect.

Expression and role of Roundabout-1 in embryonic Xenopus forebrain.

The receptor Roundabout-1 (Robo1) and its ligand Slit are known to influence axon guidance and central nervous system (CNS) patterning in both vertebrate and nonvertebrate systems. Although Robo-Slit interactions mediate axon guidance in the Drosophila CNS, their role in establishing the early axon scaffold in the embryonic vertebrate brain remains unclear. We report here the identification and expression of a Xenopus Robo1 orthologue that is highly homologous to mammalian Robo1. By using overexpression studies and immunohistochemical and in situ hybridization techniques, we have investigated the role of Robo1 in the development of a subset of neurons and axon tracts in the Xenopus forebrain. Robo1 is expressed in forebrain nuclei and in neuroepithelial cells underlying the main axon tracts. Misexpression of Robo1 led to aberrant development of axon tracts as well as the ectopic differentiation of forebrain neurons. These results implicate Robo1 in both neuronal differentiation and axon guidance in embryonic vertebrate forebrain.