The Wilms Tumor Gene wt1a Contributes to Blood-Cerebrospinal Fluid Barrier Function in Zebrafish

The Wilms tumor suppressor gene Wt1 encodes a zinc finger transcription factor, which is highly conserved among vertebrates. It is a key regulator of urogenital development and homeostasis but also plays a role in other organs including the spleen and the heart. More recently additional functions for Wt1 in the mammalian central nervous system have been described. In contrast to mammals, bony fish possess two paralogous Wt1 genes, namely wt1a and wt1b. By performing detailed in situ hybridization analyses during zebrafish development, we discovered new expression domains for wt1a in the dorsal hindbrain, the caudal medulla and the spinal cord. Marker analysis identified wt1a expressing cells of the dorsal hindbrain as ependymal cells of the choroid plexus in the myelencephalic ventricle. The choroid plexus acts as a blood-cerebrospinal fluid barrier and thus is crucial for brain homeostasis. By employing wt1a mutant larvae and a dye accumulation assay with fluorescent tracers we demonstrate that Wt1a is required for proper choroid plexus formation and function. Thus, Wt1a contributes to the barrier properties of the choroid plexus in zebrafish, revealing an unexpected role for Wt1 in the zebrafish brain.

FGF19 in the Hindbrain Lowers Blood Glucose and Alters Excitability of Vagal Motor Neurons in Hyperglycemic Mice

Fibroblast growth factor 19 (FGF19) is a protein hormone that produces antidiabetic effects when administered intracerebroventricularly in the forebrain. However, no studies have examined how FGF19 affects hindbrain neurons that participate directly in autonomic control of systemic glucose regulation. Within the dorsal hindbrain, parasympathetic motor neurons of the dorsal motor nucleus of the vagus (DMV) express fibroblast growth factor receptors and their activity regulates visceral homeostatic processes, including energy balance. This study tested the hypothesis that FGF19 acts in the hindbrain to alter DMV neuron excitability and lower blood glucose concentration. Fourth ventricle administration of FGF19 produced no effect on blood glucose concentration in control mice, but induced a significant, peripheral muscarinic receptor-dependent decrease in systemic hyperglycemia for up to 12 h in streptozotocin-treated mice, a model of type 1 diabetes. Patch-clamp recordings from DMV neurons in vitro revealed that FGF19 application altered synaptic and intrinsic membrane properties of DMV neurons, with the balance of FGF19 effects being significantly modified by a recent history of systemic hyperglycemia. These findings identify central parasympathetic circuitry as a novel target for FGF19 and suggest that FGF19 acting in the dorsal hindbrain can alter vagal output to produce its beneficial metabolic effects.

Intradiploic occipital pseudomeningocele in a patient with remote history of surgical treatment of Chiari malformation

An intradiploic CSF pseudocyst is a rare entity that has been described in association with trauma, as a sequela of untreated hydrocephalus, or occasionally as a congenital finding in older adults. The authors present the case of a woman with a remote history of a posterior fossa intradural procedure, in which she underwent Chiari malformation decompression, Silastic substitute–assisted duraplasty, and occipitocervical fusion; she presented 19 years later with recurrent symptoms of Chiari malformation. She was found to have an occipital intradiploic pseudomeningocele, arising within her dorsal occipitocervical fusion mass and resulting in dorsal hindbrain compression. She underwent a posterior fossa decompression and revision of her failed duraplasty, and she had a good recovery. This case demonstrates intradiploic CSF pseudomeningocele as a rare potential delayed complication of an intradural procedure for the treatment of Chiari malformation with occipitocervical fusion.

Elevated corticosterone in the dorsal hindbrain increases plasma norepinephrine and neuropeptide Y, and recruits a vasopressin response to stress

Repeated stress and chronically elevated glucocorticoids cause exaggerated cardiovascular responses to novel stress, elevations in baseline blood pressure, and increased risk for cardiovascular disease. We hypothesized that elevated corticosterone (Cort) within the dorsal hindbrain (DHB) would: 1) enhance arterial pressure and neuroendocrine responses to novel and repeated restraint stress, 2) increase c-Fos expression in regions of the brain involved in sympathetic stimulation during stress, and 3) recruit a vasopressin-mediated blood pressure response to acute stress. Small pellets made of 10% Cort were implanted on the surface of the DHB in male Sprague-Dawley rats. Blood pressure was measured by radiotelemetry. Cort concentration was increased in the DHB in Cort-treated compared with Sham-treated rats (60 ± 15 vs. 14 ± 2 ng Cort/g of tissue, P < 0.05). DHB Cort significantly increased the integrated arterial pressure response to 60 min of restraint stress on days 6, 13, and 14 following pellet implantation (e.g., 731 ± 170 vs. 1,204 ± 68 mmHg/60 min in Sham- vs. Cort-treated rats, day 6, P < 0.05). Cort also increased baseline blood pressure by day 15 (99 ± 2 vs. 108 ± 3 mmHg for Sham- vs. Cort-treated rats, P < 0.05) and elevated baseline plasma norepinephrine and neuropeptide Y concentrations. Cort significantly enhanced stress-induced c-Fos expression in vasopressin-expressing neurons in the paraventricular nucleus of the hypothalamus, and blockade of peripheral vasopressin V1 receptors attenuated the effect of DHB Cort to enhance the blood pressure response to restraint. These data indicate that glucocorticoids act within the DHB to produce some of the adverse cardiovascular consequences of chronic stress, in part, by a peripheral vasopressin-dependent mechanism.