Browsing by Author "Shim, Joon W."

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    Excess HB-EGF, which promotes VEGF signaling, leads to hydrocephalus
    (Nature Publishing Group, 2016-05-31) Shim, Joon W.; Sandlund, Johanna; Hameed, Mustafa Q.; Blazer-Yost, Bonnie L.; Zhou, Feng C.; Klagsbrun, Michael; Madsen, Joseph R.; Department of Anatomy & Cell Biology, IU School of Medicine
    Heparin binding epidermal growth factor-like growth factor (HB-EGF) is an angiogenic factor mediating radial migration of the developing forebrain, while vascular endothelial growth factor (VEGF) is known to influence rostral migratory stream in rodents. Cell migratory defects have been identified in animal models of hydrocephalus; however, the relationship between HB-EGF and hydrocephalus is unclear. We show that mice overexpressing human HB-EGF with β-galactosidase reporter exhibit an elevated VEGF, localization of β-galactosidase outside the subventricular zone (SVZ), subarachnoid hemorrhage, and ventriculomegaly. In Wistar polycystic kidney rats with hydrocephalus, alteration of migratory trajectory is detected. Furthermore, VEGF infusions into the rats result in ventriculomegaly with an increase of SVZ neuroblast in rostral migratory stream, whereas VEGF ligand inhibition prevents it. Our results support the idea that excess HB-EGF leads to a significant elevation of VEGF and ventricular dilatation. These data suggest a potential pathophysiological mechanism that elevated HB-EGF can elicit VEGF induction and hydrocephalus.
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    Hydrocephalus in a rat model of Meckel Gruber syndrome with a TMEM67 mutation
    (Springer Nature, 2019-01-31) Shim, Joon W.; Territo, Paul R.; Simpson, Stefanie; Watson, John C.; Jiang, Lei; Riley, Amanda A.; McCarthy, Brian; Persohn, Scott; Fulkerson, Daniel; Blazer-Yost, Bonnie L.; Biology, School of Science
    Transmembrane protein 67 (TMEM67) is mutated in Meckel Gruber Syndrome type 3 (MKS3) resulting in a pleiotropic phenotype with hydrocephalus and renal cystic disease in both humans and rodent models. The precise pathogenic mechanisms remain undetermined. Herein it is reported for the first time that a point mutation of TMEM67 leads to a gene dose-dependent hydrocephalic phenotype in the Wistar polycystic kidney (Wpk) rat. Animals with TMEM67 heterozygous mutations manifest slowly progressing hydrocephalus, observed during the postnatal period and continuing into adulthood. These animals have no overt renal phenotype. The TMEM67 homozygous mutant rats have severe ventriculomegaly as well as severe polycystic kidney disease and die during the neonatal period. Protein localization in choroid plexus epithelial cells indicates that aquaporin 1 and claudin-1 both remain normally polarized in all genotypes. The choroid plexus epithelial cells may have selectively enhanced permeability as evidenced by increased Na+, K+ and Cl- in the cerebrospinal fluid of the severely hydrocephalic animals. Collectively, these results suggest that TMEM67 is required for the regulation of choroid plexus epithelial cell fluid and electrolyte homeostasis. The Wpk rat model, orthologous to human MKS3, provides a unique platform to study the development of both severe and mild hydrocephalus.
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    Identification of elongated cilia and chiral malformation in TMEM67 mutant brains
    (Office of the Vice Chancellor for Research, 2015-04-17) Shim, Joon W.; Territo, Paul R.; Maue, Ellen; Ahmed, Shehab; Watson, John C.; Fulkerson, Dan; Blazer-Yost, Bonnie L.
    Transmembrane protein 67 (TMEM67) is encoded by one of four syndromic encephalocele genes. In humans a mutation in TMEM67 causes Meckel Gruber Syndrome, type 3 (MKS3) which is characterized by severe encephalocele and cystic kidneys and is usually fatal in the neonatal period. MKS3 is one of a spectrum of diseases known as ciliopathies because the proteins responsible for the disease are found in cells with the primary cilia. Primary cilia are a single, hair-like organelle that is found on the apical membrane of polarized cells and is thought to be involved in formation of left-right asymmetry during development as well as mechano- and chemo-reception. Here we characterize previously unreported details of cerebral phenotype in the Wistar polycystic kidney (Wpk) rats with a TMEM67 mutation. In choroid plexus (CP) epithelia of wild type animals, TMEM67 localizes to the plasma membrane and to a region close to the basal side of CP primary cilia. In a choroid plexus cell line that forms an epithelial sheet, the TMEM67 is found intracellularly but also localizes to the junctional complexes as evidenced by β catenin co-localization. Absence of normal TMEM67 leads to elongation of primary cilia in the ependymal cells lining the cerebral ventricles of the TMEM67-/- animals indicating that this protein is involved in the regulation of cilia length. Reduced aqueduct, bilateral dilatation with fusion of lateral ventricles, swelling of the hippocampus, and altered hindbrain histoarchitecture are noted in the TMEM67-/- rats. In the heterozygous animals mild asymmetric ventriculomegaly primarily on the left side is observed during early postnatal periods and continues into adulthood. These results suggest that TMEM67 is required for cilia length control and normal development of cerebral midline that maintains the symmetry of the left and right hemispheres. The Wpk rat model, orthologous to human MKS3, provides a unique model in which to study the development of both severe (TMEM67-/-) and mild (TMEM67+/-) hydrocephalus and other developmental abnormalities that are commonly found in human patients with ciliopathies.
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    Physical Weight Loading Induces Expression of Tryptophan Hydroxylase 2 in the Brain Stem
    (2014-01) Shim, Joon W.; Dodge, Todd R.; Hammond, Max A.; Wallace, Joseph M.; Zhou, Feng C.; Yokota, Hiroki
    Sustaining brain serotonin is essential in mental health. Physical activities can attenuate mental problems by enhancing serotonin signaling. However, such activity is not always possible in disabled individuals or patients with dementia. Knee loading, a form of physical activity, has been found to mimic effects of voluntary exercise. Focusing on serotonergic signaling, we addressed a question: Does local mechanical loading to the skeleton elevate expression of tryptophan hydroxylase 2 (tph2) that is a rate-limiting enzyme for brain serotonin? A 5 min knee loading was applied to mice using 1 N force at 5 Hz for 1,500 cycles. A 5-min treadmill running was used as an exercise (positive) control, and a 90-min tail suspension was used as a stress (negative) control. Expression of tph2 was determined 30 min – 2 h in three brain regions ––frontal cortex (FC), ventromedial hypothalamus (VMH), and brain stem (BS). We demonstrated for the first time that knee loading and treadmill exercise upregulated the mRNA level of tph2 in the BS, while tail suspension downregulated it. The protein level of tph2 in the BS was also upregulated by knee loading and downregulated by tail suspension. Furthermore, the downregulation of tph2 mRNA by tail suspension can be partially suppressed by pre-application of knee loading. The expression of tph2 in the FC and VMH was not significantly altered with knee loading. In this study we provided evidence that peripheral mechanical loading can activate central tph2 expression, suggesting that physical cues may mediate tph2-cathalyzed serotonergic signaling in the brain.
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    TRPV4 antagonists ameliorate ventriculomegaly in a rat model of hydrocephalus
    (American Society for Clinical Investigation, 2020-09-17) Hochstetler, Alexandra E.; Smith, Hillary M.; Preston, Daniel C.; Reed, Makenna M.; Territo, Paul R.; Shim, Joon W.; Fulkerson, Daniel; Blazer-Yost, Bonnie L.; Biology, School of Science
    Hydrocephalus is a serious condition that impacts patients of all ages. The standards of care are surgical options to divert, or inhibit production of, cerebrospinal fluid; to date, there are no effective pharmaceutical treatments, to our knowledge. The causes vary widely, but one commonality of this condition is aberrations in salt and fluid balance. We have used a genetic model of hydrocephalus to show that ventriculomegaly can be alleviated by inhibition of the transient receptor potential vanilloid 4, a channel that is activated by changes in osmotic balance, temperature, pressure and inflammatory mediators. The TRPV4 antagonists do not appear to have adverse effects on the overall health of the WT or hydrocephalic animals.