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https://www.readbyqxmd.com/read/28088536/targeting-sonic-hedgehog-signaling-in-neurological-disorders
#1
REVIEW
Sita Sharan Patel, Sunil Tomar, Diksha Sharma, Neeraj Mahindroo, Malairaman Udayabanu
Sonic hedgehog (Shh) signaling influences neurogenesis and neural patterning during the development of central nervous system. Dysregulation of Shh signaling in brain leads to neurological disorders like autism spectrum disorder, depression, dementia, stroke, Parkinson's diseases, Huntington's disease, locomotor deficit, epilepsy, demyelinating disease, neuropathies as well as brain tumors. The synthesis, processing and transport of Shh ligand as well as the localization of its receptors and signal transduction in the central nervous system has been carefully reviewed...
January 11, 2017: Neuroscience and Biobehavioral Reviews
https://www.readbyqxmd.com/read/28077400/differential-expression-of-hedgehog-and-snail-in-cutaneous-fibrosing-disorders-implications-for-targeted-inhibition
#2
Amrita Goyal, Katy R Linskey, Jonathan Kay, Lyn M Duncan, Rosalynn M Nazarian
OBJECTIVES: To examine Hedgehog signaling in cutaneous fibrosing disorders for which effective approved therapies are lacking, expand our knowledge of pathophysiology, and explore the rationale for targeted inhibition. METHODS: Stain intensity and percentage of cells staining for Sonic hedgehog (Shh), Indian hedgehog (Ihh), Patched (Ptch), glycogen synthase kinase 3 β (GSK3-β), β-catenin, and Snail were evaluated in human skin biopsy specimens of keloid, hypertrophic scar (Hscar), scleroderma, nephrogenic systemic fibrosis (NSF), scar, and normal skin using a tissue microarray...
December 2016: American Journal of Clinical Pathology
https://www.readbyqxmd.com/read/28073938/sonic-hedgehog-guides-axons-via-zipcode-binding-protein-1-mediated-local-translation
#3
Lea Lepelletier, Sébastien D Langlois, Christopher B Kent, Kristy Welshhans, Steves Morin, Gary J Bassell, Patricia T Yam, Frédéric Charron
: Sonic hedgehog (Shh) attracts spinal cord commissural axons toward the floorplate. How Shh elicits changes in the growth cone cytoskeleton that drive growth cone turning is unknown. We find that the turning of rat commissural axons up a Shh gradient requires protein synthesis. In particular, Shh stimulation increases β-actin protein at the growth cone, even when the cell bodies have been removed. Thus Shh induces the local translation of β-actin at the growth cone. We hypothesised that this requires zipcode binding protein 1 (ZBP1), an mRNA binding protein that transports β-actin mRNA and releases it for local translation upon phosphorylation...
January 10, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28069795/intraflagellar-transport-88-ift88-is-crucial-for-craniofacial-development-in-mice-and-is-a-candidate-gene-for-human-cleft-lip-and-palate
#4
Hua Tian, Jifan Feng, Jingyuan Li, Thach-Vu Ho, Yuan Yuan, Yang Liu, Frederick Brindopke, Jane C Figueiredo, William Magee, Pedro A Sanchez-Lara, Yang Chai
Ciliopathies are pleiotropic human diseases resulting from defects of the primary cilium, and these patients often have cleft lip and palate. IFT88 is required for the assembly and function of the primary cilia, which mediate the activity of key developmental signaling pathways. Through whole exome sequencing of a family of three affected siblings with isolated cleft lip and palate, we discovered that they share a novel missense mutation in IFT88 (c.915G>C, p.E305D), suggesting this gene should be considered a candidate for isolated orofacial clefting...
January 9, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28069742/islet1-dependent-%C3%AE-catenin-hedgehog-signaling-is-required-for-outgrowth-of-the-lower-jaw
#5
Feixue Li, Guoquan Fu, Ying Liu, Xiaoping Miao, Yan Li, Xueqin Yang, Xiaoyun Zhang, Dongliang Yu, Lin Gan, Mengsheng Qiu, Yiping Chen, Ze Zhang, Zunyi Zhang
Mandibular patterning information initially resides in the epithelium during development. However, how transcriptional regulation of epithelial-derived signaling controls morphogenesis of the mandible remains elusive. Using Shh(Cre) to target the mandibular epithelium, we ablated transcription factor Islet1, resulting in a distally truncated mandible via unbalanced cell apoptosis and decreased cell proliferation in the distal mesenchyme. Loss of Islet1 caused a lack of cartilage at the distal tip, leading to the two growing mandibular elements to be fused surrounding the rostral process of Meckels cartilage...
January 9, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28069589/analysis-of-the-fgfr2c342y-mouse-model-shows-condensation-defects-due-to-misregulation-of-sox9-expression-in-prechondrocytic-mesenchyme
#6
Emma Peskett, Samin Kumar, William Baird, Janhvi Jaiswal, Ming Li, Priyanca Patel, Jonathan A Britto, Erwin Pauws
Syndromic craniosynostosis caused by mutations in FGFR2 is characterised by developmental pathology in both endochondral and membranous skeletogenesis. Detailed phenotypic characterisation of features in the membranous calvarium, the endochondral cranial base and other structures in the axial and appendicular skeleton has not been performed at embryonic stages. We investigated bone development in the Crouzon mouse model (Fgfr2(C342Y)) at pre- and post-ossification stages to improve understanding of the underlying pathogenesis...
January 9, 2017: Biology Open
https://www.readbyqxmd.com/read/28065797/characterising-the-developmental-profile-of-hesc-derived-medium-spiny-neuron-progenitors-and-assessing-mature-neuron-function-using-a-crispr-generated-human-darpp-32-wt-egfp-amp-reporter-line
#7
C P J Hunt, C W Pouton, J M Haynes
In the developing ventral telencephalon, cells of the lateral ganglionic eminence (LGE) give rise to all medium spiny neurons (MSNs). This development occurs in response to a highly orchestrated series of morphogenetic stimuli that pattern the resultant neurons as they develop. Striatal MSNs are characterised by expression of dopamine receptors, dopamine-and cyclic AMP-regulated phosphoprotein (DARPP32) and the neurotransmitter GABA. In this study, we demonstrate that fine tuning WNT and SHH signaling early in human embryonic stem cell differentiation can induce a subpallial progenitor molecular profile...
January 5, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28058596/comparative-analysis-of-mutational-profile-of-sonic-hedgehog-gene-in-gallbladder-cancer
#8
Ruhi Dixit, Manoj Pandey, Sunil Kumar Tripathi, Amit Nandan Dhar Dwivedi, Vijay Kumar Shukla
BACKGROUND: Gallbladder cancer has high incidence in northeastern India; mortality too is high as the disease is often diagnosed late. Numerous studies have shown the role of sonic hedgehog (shh) in different cancers, an important ligand of the hedgehog signaling pathway. AIM: This study was carried out to evaluate the shh gene mutations in gallbladder cancer patients. METHODS: PCR-SSCP was performed for shh gene in 50 samples each of gallbladder cancer, cholelithiasis, and control...
January 5, 2017: Digestive Diseases and Sciences
https://www.readbyqxmd.com/read/28052872/fgfr2-is-integral-for-bladder-mesenchyme-patterning-and-function
#9
Youko Ikeda, Irina Zabbarova, Caitlin M Schaefer, Daniel S Bushnell, William C de Groat, Anthony J Kanai, Carlton M Bates
BACKGROUND: While urothelial signals, including sonic hedgehog (Shh), drive bladder mesenchyme differentiation, it is unclear which pathways within the mesenchyme are critical for its development. Studies have shown fibroblast growth factor receptor 2 (Fgfr2) is necessary for kidney and ureter mesenchymal development. OBJECTIVE: Out objective was to determine the role of Fgfr2 in bladder mesenchyme. METHODS: We used Tbx18cre mice to delete Fgfr2 in bladder mesenchyme (Fgfr2BM-/-)...
January 4, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28049658/stage-and-subunit-specific-functions-of-polycomb-repressive-complex-2-in-bladder-urothelial-formation-and-regeneration
#10
Chunming Guo, Zarine R Balsara, Warren G Hill, Xue Li
Urothelium is the protective lining of the urinary tract. The mechanisms underlying urothelial formation and maintenance are largely unknown. Here, we report the stage-specific roles of PRC2 epigenetic regulators in embryonic and adult urothelial progenitors. Without Eed, the obligatory subunit of PRC2, embryonic urothelial progenitors demonstrate reduced proliferation with concomitant dysregulation of genes including Cdkn2a(p16), Cdkn2b(p15) and Shh. These mutants display premature differentiation of Keratin 5-positive (Krt5(+)) basal cells and ectopic expression of squamous-like differentiation markers...
January 3, 2017: Development
https://www.readbyqxmd.com/read/28045533/computational-model-of-secondary-palate-fusion-and-disruption
#11
M Shane Hutson, Maxwell C K Leung, Nancy Baker, Richard M Spencer, Thomas B Knudsen
Morphogenetic events are driven by cell-generated physical forces and complex cellular dynamics. To improve our capacity to predict developmental effects from chemical-induced cellular alterations, we built a multi-cellular agent-based model in CompuCell3D that recapitulates the cellular networks and collective cell behavior underlying growth and fusion of the mammalian secondary palate. The model incorporated multiple signaling pathways (TGFβ, BMP, FGF, EGF, SHH) in a biological framework to recapitulate morphogenetic events from palatal outgrowth through midline fusion...
January 3, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28040834/aldehyde-dehydrogenase-activity-plays-no-functional-role-in-stem-cell-like-properties-in-anaplastic-thyroid-cancer-cell-lines
#12
Mika Shimamura, Tomomi Kurashige, Norisato Mitsutake, Yuji Nagayama
Recent studies have revealed that aldehyde dehydrogenase (ALDH) is a candidate marker for thyroid cancer stem cells, although its activity is flexible. The goal of this study is to clarify the functional significance of ALDH enzymatic activity on thyroid cancer stem cells properties in anaplastic thyroid cancer cell lines. In vitro sphere formation assay was used to judge the stemness of 4 anaplastic thyroid cancer cell lines (FRO, ACT1, 8505C, and KTC3). Two well-known ALDH inhibitors, N,N-diethylaminobenzaldehyde (DEAB) and disulfiram (DS), were first used...
December 31, 2016: Endocrine
https://www.readbyqxmd.com/read/28035386/microduplication-of-7q36-3-encompassing-the-shh-long%C3%A2-range-regulator-zrs-in-a-patient-with-triphalangeal-thumb%C3%A2-polysyndactyly-syndrome-and-congenital-heart-disease
#13
Zhenghua Liu, Ni Yin, Lianghui Gong, Zhiping Tan, Bangliang Yin, Yifeng Yang, Cheng Luo
Triphalangeal thumb‑polysyndactyly syndrome (TPT‑PS) is an autosomal dominant disorder with complete penetrance and a variable expression consisting of opposable triphalangeal thumbs, duplication of the distal thumb phalanx, pre‑axial polydactyly and duplication of the big toes (hallux). The causative gene of TPT‑PS has been mapped to 7q36.3. Sonic hedgehog (SHH) expressed in the zone of polarizing activity (ZPA) has an important role in defining the anterior‑posterior axis and numbers of digits in limb bud development...
December 29, 2016: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28031228/reprogramming-medulloblastoma-propagating-cells-via-combined-antagonism-of-sonic-hedgehog-and-cxcr4
#14
Stacey A Ward, Nicole M Warrington, Sara Taylor, Najla Kfoury, Jingqin Luo, Joshua B Rubin
The CXCR4 chemokine and sonic hedgehog (SHH) morphogen pathways are validated therapeutic targets in many cancer types, including medulloblastoma. However, single agent treatments with SHH or CXCR4 antagonists have not proven efficacious in clinical trials to date. Here we show that dual inhibition of the SHH and CXCR4 pathways exerts potent antitumor effects in a murine model of SHH-subtype medulloblastoma. This therapeutic synergy resulted in suppression of tumor-propagating cell function and correlated with increased histone H3 lysine 27 trimethylation within the promoters of stem cell genes, resulting in their decreased expression...
December 28, 2016: Cancer Research
https://www.readbyqxmd.com/read/28030564/poorly-differentiated-medullary-phenotype-predicts-poor-survival-in-early-lymph-node-negative-gastro-esophageal-adenocarcinomas
#15
Christoph Treese, Pedro Sanchez, Patricia Grabowski, Erika Berg, Hendrik Bläker, Martin Kruschewski, Oliver Haase, Michael Hummel, Severin Daum
BACKGROUND: 5-year survival rate in patients with early adenocarcinoma of the gastro-esophageal junction or stomach (AGE/S) in Caucasian patients is reported to be 60-80%. We aimed to identify prognostic markers for patients with UICC-I without lymph-node involvement (N0). METHODS: Clinical data and tissue specimen from patients with AGE/S stage UICC-I-N0, treated by surgery only, were collected retrospectively. Tumor size, lymphatic vessel or vein invasion, grading, classification systems (WHO, Lauren, Ming), expression of BAX, BCL-2, CDX2, Cyclin E, E-cadherin, Ki-67, TP53, TP21, SHH, Survivin, HIF1A, TROP2 and mismatch repair deficiency were analyzed using tissue microarrays and correlated with overall and tumor related survival...
2016: PloS One
https://www.readbyqxmd.com/read/28009451/sonic-hedgehog-is-present-in-parotid-saliva-and-is-decreased-in-patients-with-taste-dysfunction
#16
Robert I Henkin, Alexandra B Knöppel, Mona Abdelmeguid, William A Stateman, Suzanna Hosein
PURPOSE: To demonstrate that sonic hedgehog (Shh) is present in human parotid saliva and is decreased in human taste dysfunction. METHODS: Shh was measured in parotid saliva of 27 normal subjects and 81 patients with taste dysfunction of multiple etiologies by use of a sensitive spectrophotometric ELISA assay. Taste dysfunction was defined clinically by both subjective decreases of taste acuity and flavor perception and by impaired gustometry. RESULTS: Shh was found in parotid saliva in both normal subjects and in patients with taste dysfunction...
December 23, 2016: Journal of Oral Pathology & Medicine
https://www.readbyqxmd.com/read/28008008/spatiotemporal-antagonism-in-mesenchymal-epithelial-signaling-in-sweat-versus-hair-fate-decision
#17
Catherine P Lu, Lisa Polak, Brice E Keyes, Elaine Fuchs
The gain of eccrine sweat glands in hairy body skin has empowered humans to run marathons and tolerate temperature extremes. Epithelial-mesenchymal cross-talk is integral to the diverse patterning of skin appendages, but the molecular events underlying their specification remain largely unknown. Using genome-wide analyses and functional studies, we show that sweat glands are specified by mesenchymal-derived bone morphogenetic proteins (BMPs) and fibroblast growth factors that signal to epithelial buds and suppress epithelial-derived sonic hedgehog (SHH) production...
December 23, 2016: Science
https://www.readbyqxmd.com/read/27989796/altered-sox9-genital-tubercle-enhancer-region-in-hypospadias
#18
REVIEW
Rajini Sreenivasan, Christopher T Gordon, Sabina Benko, Robb de Iongh, Stefan Bagheri-Fam, Stanislas Lyonnet, Vincent Harley
Human mutations in the SOX9 gene or its regulatory region can disrupt testicular development, leading to disorders of sex development (DSDs). Our previous work involving the genomic analysis of isolated DSD patients revealed a 78kb minimal sex determining region (RevSex) far upstream of SOX9 that was duplicated in 46,XX and deleted in 46,XY DSDs. It was postulated that RevSex contains a gonadal enhancer. However, the most highly conserved sub-region within RevSex, called SR4, was neither responsive to sex determining factors in vitro nor active in the gonads of transgenic mice, suggesting that SR4 may not be functioning as a testicular enhancer...
October 28, 2016: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/27987378/in-vitro-differentiation-of-neural-stem-cells-derived-from-human-olfactory-bulb-into-dopaminergic-like-neurons
#19
Rafieh Alizadeh, Gholamreza Hassanzadeh, Mohammad Taghi Joghataei, Mansoureh Soleimani, Fatemeh Moradi, Shahram Mohammadpour, Jahangir Ghorbani, Ali Safavi, Maryam Sarbishegi, Vahid Pirhajati Mahabadi, Leila Alizadeh, Mahmoudreza Hadjighassem
Obtaining new accessible source of neuronal stem cells that can be used in Parkinson's disease cell transplant is the aim of this research. The human olfactory bulb contains neural stem cells (NSCs) that are responsible for the neurogenesis in the brain and the replacement of damaged cellular components throughout life. NSCs are capable of differentiating into neuronal and glial cells. We isolated NSCs from brain-death donor's olfactory bub and differentiate them to dopaminergic neurons. The obtained olfactory bulb tissues were cultured in DMEM12, B27 supplemented with bFGF, EGF, and LIF...
December 17, 2016: European Journal of Neuroscience
https://www.readbyqxmd.com/read/27984541/crosstalk-between-notch-and-sonic-hedgehog-signaling-in-a-mouse-model-of-amyotrophic-lateral-sclerosis
#20
Xiaoxing Ma, Anna Drannik, Fan Jiang, Randy Peterson, John Turnbull
The developmental morphogen Sonic hedgehog (Shh) may continue to play a sustaining role in adult motor neurons, of potential relevance to motor neuron diseases including amyotrophic lateral sclerosis. The Shh signaling pathway is incompletely understood and interactions with other signaling pathways are possible. We focus here on Notch, and first show that there is an almost linear reduction in light output from a Gli reporter in Shh Light II cells in the presence of increasing concentrations of the Notch inhibitor DAPT (r=0...
December 15, 2016: Neuroreport
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