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https://www.readbyqxmd.com/read/29792854/bergmann-glial-sonic-hedgehog-signaling-activity-is-required-for-proper-cerebellar-cortical-expansion-and-architecture
#1
Frances Y Cheng, Jonathan T Fleming, Chin Chiang
Neuronal-glial relationships play a critical role in the maintenance of central nervous system architecture and neuronal specification. A deeper understanding of these relationships can elucidate cellular cross-talk capable of sustaining proper development of neural tissues. In the cerebellum, cerebellar granule neuron precursors (CGNPs) proliferate in response to Purkinje neuron-derived Sonic hedgehog (Shh) before ultimately exiting the cell cycle and migrating radially along Bergmann glial fibers. However, the function of Bergmann glia in CGNP proliferation remains not well defined...
May 21, 2018: Developmental Biology
https://www.readbyqxmd.com/read/29789719/selective-vulnerability-of-the-primitive-meningeal-layer-to-prenatal-smo-activation-for-skull-base-meningothelial-meningioma-formation
#2
Julien Boetto, Caroline Apra, Franck Bielle, Matthieu Peyre, Michel Kalamarides
Somatic activating mutations of smoothened (SMO), a component of the embryonic sonic hedgehog (SHH) signaling pathway, are found in 3-5% of grade I meningiomas, most of them corresponding to meningothelial meningiomas located at the anterior skull base. By generating different developmental stage-specific conditional activations in mice, we define a restricted developmental window during which conditional activation of Smo in Prostaglandin D2-synthase-positive mesoderm-derived meningeal layer of the skull base results in meningothelial meningioma formation...
May 22, 2018: Oncogene
https://www.readbyqxmd.com/read/29787797/developing-neurites-from-mouse-basal-forebrain-gonadotropin-releasing-hormone-neurons-use-sonic-hedgehog-to-modulate-their-growth
#3
C L Tan, P W Sheard, C L Jasoni
Hypothalamic gonadotropin-releasing hormone (GnRH) neurons are required for fertility in all mammalian species studied to date. GnRH neuron cell bodies reside in the basal forebrain, and most extend long neurites in the caudal direction to terminate at the median eminence (ME), the site of hormone secretion. Using in vitro neurite growth assays, histological methods, and genetic deletion strategies in mice we have analysed the role of the morphogen and neurite growth and guidance molecule, Sonic hedgehog (Shh), in the growth of GnRH neurites to their target...
May 19, 2018: International Journal of Developmental Neuroscience
https://www.readbyqxmd.com/read/29784673/formation-of-the-sacrum-requires-down-regulation-of-sonic-hedgehog-signaling-in-the-sacral-intervertebral-discs
#4
Raffaella Bonavita, Kathleen Vincent, Robert Pinelli, Chitra Lekha Dahia
In humans, the sacrum forms an important component of the pelvic arch, and it transfers the weight of the body to the lower limbs. The sacrum is formed by collapse of the intervertebral discs (IVDs) between the five sacral vertebrae during childhood, and their fusion to form a single bone. We show that collapse of the sacral discs in the mouse is associated with the down-regulation of sonic hedgehog (SHH) signaling in the nucleus pulposus (NP) of the disc, and many aspects of this phenotype can be reversed by experimental postnatal activation of HH signaling...
May 21, 2018: Biology Open
https://www.readbyqxmd.com/read/29778738/risk-adapted-therapy-for-young-children-with-medulloblastoma-sjyc07-therapeutic-and-molecular-outcomes-from-a-multicentre-phase-2-trial
#5
Giles W Robinson, Vasilisa A Rudneva, Ivo Buchhalter, Catherine A Billups, Sebastian M Waszak, Kyle S Smith, Daniel C Bowers, Anne Bendel, Paul G Fisher, Sonia Partap, John R Crawford, Tim Hassall, Daniel J Indelicato, Frederick Boop, Paul Klimo, Noah D Sabin, Zoltan Patay, Thomas E Merchant, Clinton F Stewart, Brent A Orr, Jan O Korbel, David T W Jones, Tanvi Sharma, Peter Lichter, Marcel Kool, Andrey Korshunov, Stefan M Pfister, Richard J Gilbertson, Robert P Sanders, Arzu Onar-Thomas, David W Ellison, Amar Gajjar, Paul A Northcott
BACKGROUND: Young children with medulloblastoma have a poor overall survival compared with older children, due to use of radiation-sparing therapy in young children. Radiotherapy is omitted or reduced in these young patients to spare them from debilitating long-term side-effects. We aimed to estimate event-free survival and define the molecular characteristics associated with progression-free survival in young patients with medulloblastoma using a risk-stratified treatment strategy designed to defer, reduce, or delay radiation exposure...
May 16, 2018: Lancet Oncology
https://www.readbyqxmd.com/read/29777201/novel-smoothened-inhibitors-for-therapeutic-targeting-of-na%C3%A3-ve-and-drug-resistant-hedgehog-pathway-driven-cancers
#6
Qing-Rou Li, Hui Zhao, Xue-Sai Zhang, Henk Lang, Ker Yu
The G protein-coupled receptor (GPCR) smoothened (SMO) is a key signaling component of the sonic hedgehog (Hh) pathway and a clinically validated target for cancer treatment. The FDA-approved SMO inhibitors GDC-0449/Vismodegib and LDE225/Sonidegib demonstrated clinical antitumor efficacy. Nevertheless, relatively high percentage of treated patients would eventually develop acquired cross resistance to both drugs. Here, based on published structure and activity of GDC-0449 inhibitor class, we replaced its amide core with benzimidazole which retained bulk of the SMO-targeting activity as measured in our Hh/SMO/Gli1-reporter system...
May 18, 2018: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29776636/molecular-diagnostics-in-the-neoplasms-of-the-pancreas-liver-gallbladder-and-extrahepatic-biliary-tract-2018-update
#7
REVIEW
Lei Zhang, Martin H Bluth, Amarpreet Bhalla
Pancreatic neoplasms, including ductal adenocarcinoma, solid pseudopapillary neoplasm, pancreatic endocrine neoplasms, acinar cell carcinoma, and pancreatoblastoma, are associated with different genetic abnormalities. Hepatic adenomas with beta-catenin exon 3 mutation are associated with a high risk of malignancy. Hepatic adenoma with arginosuccinate synthetase 1 expression or sonic hedgehog mutations are associated with a risk of bleeding. Hepatocellular carcinoma and choangiocarcinoma display heterogeneity at both morphologic and molecular levels Cholangiocellular carcinoma is most commonly associated with IDH 1/2 mutations...
June 2018: Clinics in Laboratory Medicine
https://www.readbyqxmd.com/read/29776351/a-computational-study-of-hedgehog-signalling-involved-in-basal-cell-carcinoma-reveals-the-potential-and-limitation-of-combination-therapy
#8
Antoine Buetti-Dinh, Rebecca Jensen, Ran Friedman
BACKGROUND: The smoothened (SMO) receptor is an essential component of the Sonic hedgehog (SHH) signalling, which is associated with the development of skin basal cell carcinoma (BCC). SMO inhibitors are indicated for BCC patients when surgical treatment or radiation therapy are not possible. Unfortunately, SMO inhibitors are not always well tolerated due to severe side effects, and their therapeutical success is limited by resistance mutations. METHODS: We investigated how common are resistance-causing mutations in two genomic databases which are not linked to BCC or other cancers, namely 1000 Genomes and ExAC...
May 18, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29773652/stromal-gli-signaling-regulates-the-activity-and-differentiation-of-prostate-stem-and-progenitor-cells
#9
Qianjin Li, Omar A Alsaidan, Sumit Rai, Meng Wu, Huifeng Shen, Zanna Beharry, Luciana L Almada, Martin E Fernandez-Zapico, Lianchun Wang, Houjian Cai
Interactions between cells in the stroma and epithelium facilitate prostate stem cell activity and tissue regeneration capacity. Numerous molecular signal transduction pathways, including the induction of sonic hedgehog (Shh) to activate the Gli transcription factors, are known to mediate the crosstalk of these two cellular compartments. However, the details of how these signaling pathways regulate prostate stem and progenitor cell activity remain elusive. Here we demonstrate that while cell autonomous epithelial Shh-Gli signaling is essential to determine the expression levels of basal cell markers and the renewal potential of epithelial stem and progenitor cells, stromal Gli signaling regulates prostate stem and progenitor cell activity by increasing the number and size of prostate spheroids in vitro...
May 17, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29771176/potential-use-of-cxcl12-cxcr4-and-sonic-hedgehog-pathways-as-therapeutic-targets-in-medulloblastoma
#10
Marla Karine Amarante, Glauco Akelinghton Freire Vitiello, Marcos Henrique Rosa, Igor Alves Mancilla, Maria Angelica Ehara Watanabe
Medulloblastoma (MB) is the most common malignant brain tumor occurring in children, and although high long-term survival rates have been reached with current therapeutic protocols, several neurological injuries are still observed among survivors. It has been shown that the development of MB is highly dependent on the microenvironment surrounding it and that the CXCL12 chemokine and its receptor, CXCR4 and the Sonic Hedgehog (SHH) pathway are crucial for cerebellar development, coordinating proliferation and migration of embryonic cells and malfunctions in these axes can lead to MB development...
May 17, 2018: Acta Oncologica
https://www.readbyqxmd.com/read/29768039/loss-of-sonic-hedgehog-gene-leads-to-muscle-development-disorder-and-megaesophagus-in-mice
#11
Xueting Jia, Li Min, Shengtao Zhu, Shutian Zhang, Xiaofeng Huang
Sonic hedgehog ( Shh) is crucial for organogenesis in the foregut. This study investigated the function of Shh at the late-gestational stage; during which, the esophagus continues to differentiate. We established cytokeratin 14 ( CK14)-Cre;Shhfl/fl mice in which the down-regulation of Shh in the epithelium occurred at approximately the same time as esophageal muscle conversion. Hematoxylin and eosin and immunohistochemical staining, with antibodies against keratin 14, Shh, patched 1 (Ptch1), Gli1, proliferating cell nuclear antigen (PCNA), α-smooth muscle actin (αSMA), high-molecular-weight caldesmon (hCD), myogenin, paired box 7 (Pax7), β3-tubulin, and protein gene product 9...
May 16, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29760202/survey-of-human-chromosome-21-gene-expression-effects-on-early-development-in-danio-rerio
#12
Sarah Edie, Norann A Zaghloul, Carmen C Leitch, Donna K Klinedinst, Janette Lebron, Joey F Thole, Andrew S McCallion, Nicholas Katsanis, Roger H Reeves
Trisomy for human chromosome 21 (Hsa21) results in Down syndrome (DS), one of the most genetically complex conditions compatible with human survival. Assessment of the physiological consequences of dosage-driven overexpression of individual Hsa21 genes during early embryogenesis and the resulting contributions to DS pathology in mammals are not tractable in a systematic way. A recent study looked loss-of-function of C. elegans orthologues of Hsa21 genes and identified ten candidates with behavioral phenotypes, but the equivalent over-expression experiment has not been done...
May 14, 2018: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/29754802/intracellular-calcium-mobilization-is-required-for-sonic-hedgehog-signaling
#13
Dana Klatt Shaw, Derrick Gunther, Michael J Jurynec, Alexis A Chagovetz, Erin Ritchie, David Jonah Grunwald
Graded Shh signaling across fields of precursor cells coordinates patterns of gene expression, differentiation, and morphogenetic behavior as precursors form complex structures, such as the nervous system, the limbs, and craniofacial skeleton. Here we discover that intracellular calcium mobilization, a process tightly controlled and readily modulated, regulates the level of Shh-dependent gene expression in responding cells and affects the development of all Shh-dependent cell types in the zebrafish embryo. Reduced expression or modified activity of ryanodine receptor (RyR) intracellular calcium release channels shifted the allocation of Shh-dependent cell fates in the somitic muscle and neural tube...
May 8, 2018: Developmental Cell
https://www.readbyqxmd.com/read/29749693/modeling-the-complex-etiology-of-holoprosencephaly-in-mice
#14
Mingi Hong, Robert S Krauss
Holoprosencephaly (HPE) is a common developmental defect caused by failure to define the midline of the forebrain and/or midface. HPE is associated with heterozygous mutations in Nodal and Sonic hedgehog (SHH) pathway components, but clinical presentation is highly variable, and many mutation carriers are unaffected. It is therefore thought that such mutations interact with more common modifiers, genetic and/or environmental, to produce severe patterning defects. Modifiers are difficult to identify, as their effects are context-dependent and occur within the complex genetic and environmental landscapes that characterize human populations...
May 11, 2018: American Journal of Medical Genetics. Part C, Seminars in Medical Genetics
https://www.readbyqxmd.com/read/29749689/functions-of-tgif-homeodomain-proteins-and-their-roles-in-normal-brain-development-and-holoprosencephaly
#15
David Wotton, Kenichiro Taniguchi
Holoprosencephaly (HPE) is a frequent human forebrain developmental disorder with both genetic and environmental causes. Multiple loci have been associated with HPE in humans, and potential causative genes at 14 of these loci have been identified. Although TGIF1 (originally TGIF, for Thymine Guanine-Interacting Factor) is among the most frequently screened genes in HPE patients, an understanding of how mutations in this gene contribute to the pathogenesis of HPE has remained elusive. However, mouse models based on loss of function of Tgif1, and the related Tgif2 gene, have shed some light on how human TGIF1 variants might cause HPE...
May 11, 2018: American Journal of Medical Genetics. Part C, Seminars in Medical Genetics
https://www.readbyqxmd.com/read/29742881/medulloblastoma-in-the-molecular-era
#16
REVIEW
Claudia Miranda Kuzan-Fischer, Kyle Juraschka, Michael D Taylor
Medulloblastoma is the most common malignant brain tumor of childhood and remains a major cause of cancer related mortality in children. Significant scientific advancements have transformed the understanding of medulloblastoma, leading to the recognition of four distinct clinical and molecular subgroups, namely wingless (WNT), sonic hedgehog, group 3, and group 4. Subgroup classification combined with the recognition of subgroup specific molecular alterations has also led to major changes in risk stratification of medulloblastoma patients and these changes have begun to alter clinical trial design, in which the newly recognized subgroups are being incorporated as individualized treatment arms...
May 2018: Journal of Korean Neurosurgical Society
https://www.readbyqxmd.com/read/29739868/the-dorsal-wave-of-neocortical-oligodendrogenesis-begins-embryonically-and-requires-multiple-sources-of-sonic-hedgehog
#17
Caitlin C Winkler, Odessa R Yabut, Santiago P Fregoso, Hector G Gomez, Brett E Dwyer, Samuel J Pleasure, Santos J Franco
Neural progenitor cells in the developing dorsal forebrain give rise to excitatory neurons, astrocytes and oligodendrocytes for the neocortex. Compared to neurons and astrocytes, less is known about the molecular mechanisms that instruct dorsal forebrain progenitors to an oligodendrocyte fate. In this study, we show that Sonic hedgehog (Shh) signaling is required in dorsal progenitors for their late embryonic transition to oligodendrogenesis. Using genetic lineage-tracing in mice of both sexes, we demonstrate that the majority of oligodendrocytes in the embryonic neocortex derive from Emx1+ dorsal forebrain progenitors...
May 8, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29738174/-hypospadias-induced-by-maternal-exposure-to-di-n-butyl-phthalate-and-its-mechanisms-in-male-rat-offspring
#18
En-Hui Li, Hai-Bin Wei, Bang-Gao Lhuangi, En-Hui Li, Qi Zhang, Zhi-Hui Xu, Da-Hong Zhang
Objective: To induce hypospadias in male rat offspring by maternal exposure to di-n-butyl phthalate (DBP) during late pregnancy and further investigate its mechanisms. METHODS: We randomly divided 20 pregnant rats into a DBP exposure and a control group, the former treated intragastrically with DBP while the latter with soybean oil at 750 mg per kilogram of the body weight per day from gestation days (GD) 14 to 18. On postnatal day (PND) 1, we recorded the incidence rate of hypospadias and observed the histopathological changes in the genital tubercle of the hypospadiac rats...
December 2017: Zhonghua Nan Ke Xue, National Journal of Andrology
https://www.readbyqxmd.com/read/29734730/glioma-associated-oncogene-homolog-inhibitors-have-the-potential-of-suppressing-cancer-stem-cells-of-breast-cancer
#19
Kuo-Shyang Jeng, Chi-Juei Jeng, I-Shyan Sheen, Szu-Hua Wu, Ssu-Jung Lu, Chih-Hsuan Wang, Chiung-Fang Chang
Overexpression of Sonic Hedgehog signaling (Shh) pathway molecules is associated with invasiveness and recurrence in breast carcinoma. Therefore, inhibition of the Shh pathway downstream molecule Glioma-associated Oncogene Homolog (Gli) was investigated for its ability to reduce progression and invasiveness of patient-derived breast cancer cells and cell lines. Human primary breast cancer T2 cells with high expression of Shh signaling pathway molecules were compared with breast cancer line MDA-MB-231 cells...
May 5, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29731823/-epigallocatechin-3-gallate-protects-pc12-cells-against-corticosterone-induced-neurotoxicity-via-the-hedgehog-signaling-pathway
#20
Sha Feng, Jue Liu, Biao Cheng, Aiping Deng, Hong Zhang
It has been acknowledged that environmental stress is a risk factor for developing mental disorders. Chronic stress may contribute to the hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis and a sustained rise in the levels of glucocorticoids (GCs). A high concentration of corticosterone (CORT) damages neuronal PC12 cells. It has been reported that (-)-Epigallocatechin-3-gallate (EGCG), a major component of green tea, exhibits neuroprotective activity. However, the protective effect of EGCG on neuronal cells injured by CORT remains to be elucidated...
May 2018: Experimental and Therapeutic Medicine
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