Near Reflex Substitution for Horizontal Gaze Palsy in a Patient With Facial Colliculus Syndrome.

Paradoxical convergence movements on attempted side gaze have been rarely reported in horizontal gaze palsy. The authors report the clinical manifestation of right-sided facial colliculus syndrome in a 9-year-old girl who manifested convergence, miosis, and myopic shift on attempting right gaze that was treated with strabismus surgery, and provide a comprehensive literature review. [J Pediatr Ophthalmol Strabismus. 2020;57:e15-e18.].

Magnetic resonance imaging findings associated with lateral cerebral ventriculomegaly in English Bulldogs.

Multiple congenital or developmental anomalies associated with the central nervous system have been reported in English Bulldogs. The purpose of this retrospective study was to identify and describe the prevalence and MRI characteristics of these anomalies and their association with presence and degree of cerebral ventriculomegaly. Magnetic resonance imaging studies of 50 English Bulldogs were evaluated. Forty-eight dogs had some degree of cerebral ventriculomegaly, 27 of which had an otherwise normal brain. Presence of lateral ventriculomegaly was not significantly associated with presence of another intracranial lesion. Appearance of the septum pellucidum was variable, ranging from intact to incomplete or completely absent. The corpus callosum was subjectively thinned in all but three dogs, two of which had normal lateral ventricles. Fusion of the rostral colliculi was not found in any dog. A persistent craniopharyngeal canal was identified in one dog. Aqueductal stenosis caused by fusion of the rostral colliculi was not identified in any dog. Findings indicated that cerebral ventriculomegaly is a common finding in English Bulldogs with or without other intracranial lesions, aqueductal stenosis caused by fusion of the rostral colliculi is unlikely to be a common etiology leading to obstructive hydrocephalus, and a large craniopharyngeal canal is a rare finding that has unknown clinical significance at this time.

Expansion, folding, and abnormal lamination of the chick optic tectum after intraventricular injections of FGF2.

Comparative research has shown that evolutionary increases in brain region volumes often involve delays in neurogenesis. However, little is known about the influence of such changes on subsequent development. To get at this question, we injected FGF2--which delays cell cycle exit in mammalian neocortex--into the cerebral ventricles of chicks at embryonic day (ED) 4. This manipulation alters the development of the optic tectum dramatically. By ED7, the tectum of FGF2-treated birds is abnormally thin and has a reduced postmitotic layer, consistent with a delay in neurogenesis. FGF2 treatment also increases tectal volume and ventricular surface area, disturbs tectal lamination, and creates small discontinuities in the pia mater overlying the tectum. On ED12, the tectum is still larger in FGF2-treated embryos than in controls. However, lateral portions of the FGF2-treated tectum now exhibit volcano-like laminar disturbances that coincide with holes in the pia, and the caudomedial tectum exhibits prominent folds. To explain these observations, we propose that the tangential expansion of the ventricular surface in FGF2-treated tecta outpaces the expansion of the pial surface, creating abnormal mechanical stresses. Two alternative means of alleviating these stresses are tectal foliation and the formation of pial holes. The latter probably alter signaling gradients required for normal cell migration and may generate abnormal patterns of cerebrospinal fluid flow; both abnormalities would generate disturbances in tectal lamination. Overall, our findings suggest that evolutionary expansion of sheet-like, laminated brain regions requires a concomitant expansion of the pia mater.

Cytoarchitectonic and neurochemical differentiation of the visual system in ethanol-induced cyclopic zebrafish larvae.

Embryonic exposure to ethanol leads to malformations such as cyclopia. Cyclopic embryos present fused eyes and lack of the ventral specification of the brain, with physiological and morphological defects in the visual system, which provides a useful model for teratology and neurotoxicity assessments. We analysed the differentiation of the visual areas in the ethanol-induced cyclopic animals. For this purpose we exposed zebrafish embryos to 1.5% ethanol from 4 hours post-fertilisation (hpf) to 24 hpf in order to get cyclopic embryos. We monitored cytoarchitecture and quantified both the proliferation rate and cell differentiation from 2 days post-fertilisation (dpf) onwards, focusing on the main components of the visual system (retina, optic nerve and optic tectum) of normal and cyclopic zebrafish embryos. The visual system of the zebrafish embryos is affected by exposure to ethanol; two optic nerves that fuse before leaving the eyes are present in cyclopic specimens but an optic chiasm is not evident. Cell differentiation is severely delayed throughout the visual system at 2 dpf. At 5 dpf, lamination in the cyclopic retina and optic tectum is completed, but they are filled with pyknotic nuclei demonstrating cell death. At this stage the proliferation rate and expression patterns are unaltered and glial and neuronal neurochemical differentiations are similar to untreated animals. We found that the alterations produced by exposure to ethanol are not only cell-selective, but also tissue-selective. Cyclopia is the most severe phenotype induced by ethanol, although cell differentiation and proliferation can reach normal patterns after a certain period of time, which points to a neural plasticity process. Zebrafish embryos may possess a compensation mechanism against the ethanol effect, which would account for their use for pharmacogenetic and chemical screenings in the analysis of new molecules that could improve visual problems.

Phenotypic analyses of a medaka mutant reveal the importance of bilaterally synchronized expression of isthmic fgf8 for bilaterally symmetric formation of the optic tectum.

Developing neural tubes are bilaterally symmetric in all vertebrate embryos, irrespective of the presence of gene networks that generate left-right asymmetry. To explore the mechanisms that underlie the bilaterally symmetric formation of the neural tube, we examined a medaka (Oryzias latipes) dominant mutant, Oot, the neural tube of which transiently lacks normal symmetry in the optic tectum. We found that spatial changes in isthmic fgf8 expression do not occur on one side of the mutant, resulting in a transient desynchronized expression that correlates with tectal asymmetry. The application of exogenous FGF8 on one side of a wild-type embryo mimics the Oot phenotype, indicating that the bilaterally equivalent expression of isthmic fgf8 is crucial for the bilaterally symmetric development of the tectum. These results suggest that tectal symmetry is not a "default" state, but rather is maintained actively by a bilaterally coupled and synchronized regulation of isthmic fgf8 expression.

Vesicular glutamate transport at a central synapse limits the acuity of visual perception in zebrafish.

The neural circuitry that constrains visual acuity in the CNS has not been experimentally identified. We show here that zebrafish blumenkohl (blu) mutants are impaired in resolving rapid movements and fine spatial detail. The blu gene encodes a vesicular glutamate transporter expressed by retinal ganglion cells. Mutant retinotectal synapses release less glutamate, per vesicle and per terminal, and fatigue more quickly than wild-type in response to high-frequency stimulation. In addition, mutant axons arborize more extensively, thus increasing the number of synaptic terminals and effectively normalizing the combined input to postsynaptic cells in the tectum. This presumably homeostatic response results in larger receptive fields of tectal cells and a degradation of the retinotopic map. As predicted, mutants have a selective deficit in the capture of small prey objects, a behavior dependent on the tectum. Our studies successfully link the disruption of a synaptic protein to complex changes in neural circuitry and behavior.

A GFP-based genetic screen reveals mutations that disrupt the architecture of the zebrafish retinotectal projection.

The retinotectal projection is a premier model system for the investigation of molecular mechanisms that underlie axon pathfinding and map formation. Other important features, such as the laminar targeting of retinal axons, the control of axon fasciculation and the intrinsic organization of the tectal neuropil, have been less accessible to investigation. In order to visualize these processes in vivo, we generated a transgenic zebrafish line expressing membrane-targeted GFP under control of the brn3c promoter/enhancer. The GFP reporter labels a distinct subset of retinal ganglion cells (RGCs), which project mainly into one of the four retinorecipient layers of the tectum and into a small subset of the extratectal arborization fields. In this transgenic line, we carried out an ENU-mutagenesis screen by scoring live zebrafish larvae for anatomical phenotypes. Thirteen recessive mutations in 12 genes were discovered. In one mutant, ddl, the majority of RGCs fail to differentiate. Three of the mutations, vrt, late and tard, delay the orderly ingrowth of retinal axons into the tectum. Two alleles of drg disrupt the layer-specific targeting of retinal axons. Three genes, fuzz, beyo and brek, are required for confinement of the tectal neuropil. Fasciculation within the optic tract and adhesion within the tectal neuropil are regulated by vrt, coma, bluk, clew and blin. The mutated genes are predicted to encode molecules essential for building the intricate neural architecture of the visual system.

The lens has a specific influence on optic nerve and tectum development in the blind cavefish Astyanax.

We used the teleost Astyanaxmexicanus to examine the role of the lens in optic nerve and tectum development. This speciesis unusually suited for studies of nervous system development and evolution because of its two extant forms: an eyed surface dwelling (surface fish) and several blind cave dwelling (cavefish) forms. Cavefish embryos initially form eye primordia, but the lens eventually dies by apoptosis, then the retina ceases to grow, and finally the degenerating eyes sink into the orbits. Transplantation of an embryonic surface fish lens into a cavefish optic cup restores eye development. We show here that retinal nerve fibers are formed and project to the optic tectum in cavefish embryos. In adult cavefish that have completed lens degeneration, however, the number of retinal axons in the optic nerve is substantially reduced compared to surface fish. The presumptive brain domains of embryonic cavefish are not altered relative to surface fish based on expression of the regional marker genes Pax6, Pax2.1, and engrailed2. In contrast, the adult cavefish brain is elongated, the optic tectum is diminished in volume, and the number of tectal neurons is reduced relative to surface fish. Unilateral transplantation of an embryonic surface fish lens into a cavefish optic cup increases the size of the optic nerve, the number of retinotectal projections from the restored eye, and the volume and neuronal content of the contralateral optic tectum. The results suggest that the lens has a specific influence on optic nerve and tectum development during eye growth in Astyanax.

Cytoarchitecture and fiber pattern of the superior colliculus are disrupted in the Shaking Rat Kawasaki.

Shaking Rat Kawasaki (SRK) is a Reelin-deficient rat, that shows significant cytoarchitectural abnormalities in the cerebral and cerebellar cortices in a similar manner to the reeler malformation. In the present study, we investigated the cytoarchitecture and myeloarchitecture of the superior colliculus (SC) of this mutant rat. The Nissl staining clearly showed that neuronal components in the superficial layers of the SC in SRK rat were intermingled with each other and that the boundaries between these superficial layers were blurred. The MBP immunohistochemistry showed an abnormal fiber pattern in the superficial layers of the SC of this mutant rat. In the normal rat, myelinated fibers passed rostrocaudally through the optic layer, and only a few myelinated fibers were recognized in the uppermost two layers, i.e., the zonal and superficial gray layers. By contrast, in SRK rat, the myelinated fibers were distributed throughout the entire thickness of the superficial layers of the SC. Anterograde labeling of retinotectal fibers with an injection of Cholera Toxin subunit B into the retina revealed that this abnormal fiber pattern was associated with the anomalous course of the retinotectal fibers. No distinct differences in the cytoarchitecture and fiber pattern in the deep layers of the SC were seen. In conclusion, the present study demonstrated that the cytoarchitecture and fiber patterning in the superficial layers of the SC were disrupted in SRK rat, suggesting that Reelin protein regulates the formation of the superficial layers of the SC.

EphB forward signaling controls directional branch extension and arborization required for dorsal-ventral retinotopic mapping.

We report that EphB receptors direct unique axonal behaviors required for mapping the dorsal-ventral (D-V) retinal axis along the lateral-medial (L-M) axis of the superior colliculus (SC). EphBs are expressed in a D-V gradient, ephrin-B1 in a L-M gradient in SC, and ephrin-B3 at its midline. EphBs and ephrin-Bs are expressed in countergradients in retina and SC. Developmental analyses reveal that retinal axons lack D-V ordering along the L-M axis, but directionally extend branches along it to establish ordered arbors. Directed branch extension is disrupted in EphB2; EphB3-deficient mice resulting in lateral ectopic arbors. Mice with kinase-inactive EphB2 have similar D-V mapping defects indicating that forward signaling dominates over reverse signaling. Our data suggest that branches of EphB expressing axons are attracted medially by ephrin-B1, and provide molecular mechanisms for D-V mapping in visual centers.

Morphological changes in the neuronal substrate for the optokinetic reflex in albino ferrets.

Albino mammals show very characteristic deficits in their optokinetic system, and albino ferrets are even optokinetically blind. To investigate the neuronal causes for this defect we compared the morphology of retinal slip cells in the pretectal nucleus of the optic tract and the dorsal terminal nucleus of the accessory optic system (NOT-DTN) in pigmented and albino ferrets (Mustela putorius furo) using retrograde tracing techniques. After tracer injections into the inferior olive, equal numbers of NOT-DTN neurons were retrogradely labelled in pigmented and albino animals. However, NOT-DTN cells in albino ferrets had fewer stem dendrites, and the cumulative dendritic length was reduced by 30% when compared with NOT-DTN neurons in pigmented animals. In addition, the prominent network formed by distal dendrites observed in the NOT-DTN of pigmented ferrets was largely diminished in albinos. Taken together with behavioural and physiological data, these findings indicate that the NOT-DTN as the main visuomotor interface in the optokinetic system is clearly defective in albino ferrets.

2, 3, 7, 8-tetrachlorodibenzo-p-dioxin induces apoptosis in the dorsal midbrain of zebrafish embryos by activation of arylhydrocarbon receptor.

Neurotoxic effects of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) has not been fully elucidated, despite the known potent agonist of arylhydrocarbon receptor (AhR), which activation induces cytochrome P450 1A and several representative toxicities of halogenated aromatic hydrocarbons. In the present study, the effects of TCDD on cell death in zebrafish embryos (Danio rerio) during the early stage of development were investigated. As shown by terminal transferase-mediated nick-end-labeling staining, TCDD exposure significantly increased the occurrence of pycnotic cell death (PCD), especially in the dorsal midbrain (optic tectum). The ultrastructures of these pycnotic cells showed apoptotic features such as condensation and cleavage of chromatin. TCDD-induced PCD was mimicked by beta-naphthoflavone (AhR agonist), and inhibited by alpha-naphthoflavone (AhR antagonist). These results suggest that AhR activation can induce apoptosis in the central nervous system during development.

Genetic analysis of ephrin-A2 and ephrin-A5 shows their requirement in multiple aspects of retinocollicular mapping.

Ephrin-A2 and -A5 are thought to be anteroposterior mapping labels for the retinotectal/retinocollicular projection. Here, gene disruptions of both these ephrins are characterized. Focal retinal labeling reveals moderate map abnormalities when either gene is disrupted. Double heterozygotes also have a phenotype, showing an influence of absolute levels. In vitro assays indicate these ephrins are required for repellent activity in the target and also normal responsiveness in the retina. In double homozygotes, anteroposterior order is almost though not completely lost. Temporal or nasal retinal labelings reveal quantitatively similar but opposite shifts, with multiple terminations scattered widely over the target. These results indicate an axon competition mechanism for mapping, with a critical role for ephrins as anteroposterior topographic labels. Dorsoventral topography is also impaired, showing these ephrins are required in mapping both axes.

Misexpression of a bHLH gene, cNSCL1, results in abnormal brain development.

NSCL1 is a basic helix-loop-helix transcription factor involved in the development of the nervous system. To elucidate its role in neurogenesis, we cloned chick NSCL1 (cNSCL1) and examined its expression pattern and the effect of its misexpression on brain development. cNSCL1 was predominantly expressed during active neurogenesis. Double-labeling experiments showed that proliferating neuroblasts in the ventricular zone lacked cNSCL1 expression and cells expressing cNSCL1 were located just outside the ventricular zone. Retroviral misexpression of cNSCL1 in chick embryos produced a brain with abnormal structure. While the forebrain of the embryonic day-12 (E12) brain appeared normal, the tectum was enlarged. The enlargement was likely due to an increase in cell proliferation, since more radioactivity was detected in this region of the brain after [3H]thymidine labeling at E9. The cerebellum, on the other hand, was reduced in size. Fewer cells were labeled with BrdU in the external granule layer (a secondary germinal layer required for cerebellum development) in experimental embryos than in the controls, suggesting that misexpression of cNSCL1 might interfere with cell proliferation in the external granular layer. Our data indicate that regulated expression of cNSCL1 is required for normal brain development. They also imply that cNSCL1 might be involved in preventing some postmitotic cells from reentering the cell cycle during neurogenesis. Dev Dyn 1999;215:238-247.

Morphological deficits in noradrenergic neurons in GEPR-9s stem from abnormalities in both the locus coeruleus and its target tissues.

The epileptic condition of the genetically epilepsy-prone rat (GEPR) appears to be caused partially by deficiencies in the locus coeruleus (LC) innervation of the superior colliculus (SC). Previous studies provide quantitative documentation of noradrenergic morphological deficits in the moderately epileptic GEPR-3. The present findings extend these studies by applying cell culture methodology to assessments of the severely epileptic GEPR-9. Our data show that total neurite length, the number of neurite branch points per cell, the cross-sectional area of cell bodies, and the cell perimeter are deficient in noradrenergic neurons in LC + SC cocultures derived exclusively from GEPR-9s compared to analogous cocultures obtained solely from nonepileptic control rats. Partial restoration of LC neuron morphology toward normal occurs when the GEPR-9 SC component of the coculture is replaced with nonepileptic control SC. Finally, when the GEPR-9 SC is cocultured with the control LC, a partial morphological deficit occurs in the otherwise normal noradrenergic neurons. However, the magnitude of this deficit is less than that observed in noradrenergic neurons of the GEPR-9 LC cocultured with the control SC. These data support the hypothesis that the developmental deficiencies of noradrenergic neurons of the GEPR-9 are derived from two sources, the LC and its target tissue, in this case, the SC. Also, intrinsic abnormalities of the LC appear to make a more pronounced contribution to the noradrenergic deficits than do those which reside in the SC.

Efficient mutagenesis of zebrafish by a DNA cross-linking agent.

We developed a novel procedure for efficient mutagenesis of zebrafish using a DNA cross-linking agent 4,5',8-trimethylpsoralen (TMP), which is known to frequently induce small deletions in Escherichia coli and Caenorhabditis elegans. A specific-locus test and pilot screenings indicated that the TMP mutagenesis procedure was efficient. To confirm the successful mutagenesis by TMP, we characterized mutants with selective impairments in the nervous system. The no tectal neuron mutation hindered the development of the tectal neurons, while the edawakare mutation resulted in the enhancement of the extension and branching of the peripheral axons of trigeminal ganglion and Rohon-Beard sensory neurons. These results suggest that the TMP mutagenesis will provide an efficient method to isolate and characterize zebrafish mutants at molecular level.

Jaw and branchial arch mutants in zebrafish I: branchial arches.

Jaws and branchial arches together are a basic, segmented feature of the vertebrate head. Seven arches develop in the zebrafish embryo (Danio rerio), derived largely from neural crest cells that form the cartilaginous skeleton. In this and the following paper we describe the phenotypes of 109 arch mutants, focusing here on three classes that affect the posterior pharyngeal arches, including the hyoid and five gill-bearing arches. In lockjaw, the hyoid arch is strongly reduced and subsets of branchial arches do not develop. Mutants of a large second class, designated the flathead group, lack several adjacent branchial arches and their associated cartilages. Five alleles at the flathead locus all lead to larvae that lack arches 4-6. Among 34 other flathead group members complementation tests are incomplete, but at least six unique phenotypes can be distinguished. These all delete continuous stretches of adjacent branchial arches and unpaired cartilages in the ventral midline. Many show cell death in the midbrain, from which some neural crest precursors of the arches originate. lockjaw and a few mutants in the flathead group, including pistachio, affect both jaw cartilage and pigmentation, reflecting essential functions of these genes in at least two neural crest lineages. Mutants of a third class, including boxer, dackel and pincher, affect pectoral fins and axonal trajectories in the brain, as well as the arches. Their skeletal phenotypes suggest that they disrupt cartilage morphogenesis in all arches. Our results suggest that there are sets of genes that: (1) specify neural crest cells in groups of adjacent head segments, and (2) function in common genetic pathways in a variety of tissues including the brain, pectoral fins and pigment cells as well as pharyngeal arches.

Cerebellar vermis and midbrain dysgenesis in oculomotor apraxia: MR findings.

The MR imaging findings in two patients with the clinical diagnosis of oculomotor apraxia are presented. Both cases showed dysgenesis of the cerebellar vermis, and the colliculi were fused in one patient. No supratentorial abnormalities were seen in either patient.

Tectocerebellar dysraphia with posterior encephalocele (Friede): report of the youngest case. Reappraisal of the condition uniting Cleland-Chiari (Arnold-Chiari) and Dandy-Walker syndromes.

This is a neuropathological report of the youngest case ever recorded of tectocerebellar dysraphia with posterior encephalocele. All previously described stigmata were ascertained as well as a few additional findings. Some morphological features of this syndrome similar to and some different from the Dandy-Walker syndrome and the Cleland-Chiari (Arnold-Chiari) anomaly are briefly discussed. Finally the possibility of clinical diagnosis and favourable prognosis of this syndrome are suggested.

MRI and clinical findings in rhombencephalosynapsis.

Rhombencephalosynapsis is an unusual disorder characterized predominantly by agenesis/hypogenesis of the cerebellar vermis and fusion of the cerebellar hemispheres. Three cases are reported with emphasis on the MRI and clinical findings. Discussion of the relative importance of the cerebellar anomalies and associated supratentorial abnormalities is included.