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Sonic Hedgehog Regulation of the Neural Precursor Cell Fate During Chicken Optic Tectum Development

Yang C, Li X, Li Q, Li H, Qiao L, Guo Z, et al.

J Mol Neurosci, 2018 Feb;64(2):287-299.
PMID: 29285739 DOI: 10.1007/s12031-017-1019-5

During nervous system development, neurons project axons over long distances to reach the appropriate targets for correct neural circuit formation. Sonic hedgehog (Shh) is a secreted protein and plays a key role in regulating vertebrate embryogenesis, especially in central nervous system (CNS) patterning, including neuronal migration and axonal projection in the brain and spinal cord. In the developing ventral midbrain, Shh is sufficient to specify a striped pattern of cell fates. Little is known about the molecular mechanisms underlying the Shh regulation of the neural precursor cell fate during the optic tectum development. Here, we aimed at studying how Shh might regulate chicken optic tectum patterning. In the present study, in ovo electroporation methods were employed to achieve the overexpression of Shh in the optic tectum during chicken embryo development. Besides, the study combined in ovo electroporation and neuron isolation culturing to study the function of Shh in vivo and in vitro. The fluorescent immunohistochemistry methods were used to check the related indicators. The results showed that Shh overexpression caused 87.8% of cells to be distributed to the stratum griseum central (SGC) layer, while only 39.3% of the GFP-transfected cells resided in the SGC layer in the control group. Shh overexpression also reduced the axon length in vivo and in vitro. In conclusion, we provide evidence that Shh regulates the neural precursor cell fate during chicken optic tectum development. Shh overexpression impairs neuronal migration and may affect the fate determination of transfected neurons.

Matched MeSH terms: Hedgehog Proteins/genetics*; Hedgehog Proteins/metabolism
Fulltext Effect of sonic hedgehog on motor neuron positioning in the spinal cord during chicken embryonic development

Yang C, Li S, Li X, Li H, Li Y, Zhang C, et al.

J Cell Mol Med, 2019 05;23(5):3549-3562.
PMID: 30834718 DOI: 10.1111/jcmm.14254

Sonic hedgehog (SHH) is a vertebrate homologue of the secreted Drosophila protein hedgehog and is expressed by the notochord and floor plate in the developing spinal cord. Sonic hedgehog provides signals relevant for positional information, cell proliferation and possibly cell survival, depending on the time and location of expression. Although the role of SHH in providing positional information in the neural tube has been experimentally proven, the underlying mechanism remains unclear. In this study, in ovo electroporation was employed in the chicken spinal cord during chicken embryo development. Electroporation was conducted at stage 17 (E2.5), after electroporation the embryos were continued incubating to stage 28 (E6) for sampling, tissue fixation with 4% paraformaldehyde and frozen sectioning. Sonic hedgehog and related protein expressions were detected by in situ hybridization and fluorescence immunohistochemistry and the results were analysed after microphotography. Our results indicate that the ectopic expression of SHH leads to ventralization in the spinal cord during chicken embryonic development by inducing abnormalities in the structure of the motor column and motor neuron integration. In addition, ectopic SHH expression inhibits the expression of dorsal transcription factors and commissural axon projections. The correct location of SHH expression is vital to the formation of the motor column. Ectopic expression of SHH in the spinal cord not only affects the positioning of motor neurons, but also induces abnormalities in the structure of the motor column. It leads to ventralization in the spinal cord, resulting in the formation of more ventral neurons forming during neuronal formation.

Matched MeSH terms: Hedgehog Proteins/genetics*; Hedgehog Proteins/metabolism
Outcomes of Infants and Young Children With Relapsed Medulloblastoma After Initial Craniospinal Irradiation-Sparing Approaches: An International Cohort Study

Erker C, Mynarek M, Bailey S, Mazewski CM, Baroni L, Massimino M, et al.

J Clin Oncol, 2023 Apr 01;41(10):1921-1932.
PMID: 36548930 DOI: 10.1200/JCO.21.02968

PURPOSE: Infant and young childhood medulloblastoma (iMB) is usually treated without craniospinal irradiation (CSI) to avoid neurocognitive late effects. Unfortunately, many children relapse. The purpose of this study was to assess salvage strategies and prognostic features of patients with iMB who relapse after CSI-sparing therapy.
METHODS: We assembled a large international cohort of 380 patients with relapsed iMB, age younger than 6 years, and initially treated without CSI. Univariable and multivariable Cox models of postrelapse survival (PRS) were conducted for those treated with curative intent using propensity score analyses to account for confounding factors.
RESULTS: The 3-year PRS, for 294 patients treated with curative intent, was 52.4% (95% CI, 46.4 to 58.3) with a median time to relapse from diagnosis of 11 months. Molecular subgrouping was available for 150 patients treated with curative intent, and 3-year PRS for sonic hedgehog (SHH), group 4, and group 3 were 60%, 84%, and 18% (P = .0187), respectively. In multivariable analysis, localized relapse (P = .0073), SHH molecular subgroup (P = .0103), CSI use after relapse (P = .0161), and age ≥ 36 months at initial diagnosis (P = .0494) were associated with improved survival. Most patients (73%) received salvage CSI, and although salvage chemotherapy was not significant in multivariable analysis, its use might be beneficial for a subset of children receiving salvage CSI < 35 Gy (P = .007).
CONCLUSION: A substantial proportion of patients with relapsed iMB are salvaged after initial CSI-sparing approaches. Patients with SHH subgroup, localized relapse, older age at initial diagnosis, and those receiving salvage CSI show improved PRS. Future prospective studies should investigate optimal CSI doses and the role of salvage chemotherapy in this population.

Matched MeSH terms: Hedgehog Proteins
Molecular Modelling of Berberine Derivatives as Inhibitors of Human Smoothened Receptor and Hedgehog Signalling Pathway Using a Newly Developed Algorithm on Anti-Cancer Drugs

Kaboli PJ, Bazrafkan M, Ismail P, Ling KH

Recent Pat Anticancer Drug Discov, 2017 Nov 20;12(4):384-400.
PMID: 28969581 DOI: 10.2174/1574892812666170929131247

BACKGROUND: Protoberberine isoquinoline alkaloids are found in many plant species. They consist of a diverse class of secondary metabolites with many pharmacologically active members, such as different derivatives of berberine already patented. In the development of approximately 20-25% of all cancers, altered hedgehog (Hh) signalling is involved where the smoothened (Smo) transmembrane receptor triggers Hh signalling pathway towards Gli1 gene expression.
OBJECTIVE: The current study aimed to model and verify the anti-Smo activity of berberine and its derivatives using a novel automated script.
METHOD: Based on the patented inventions filed on ADMET modelling until 2016, which also predicts ADMET parameters and binding efficiency indices for all molecules, a script was developed to run automated molecular docking for a large number of small molecules.
RESULTS: Berberine was found to interact with Lys395 of Smo receptor via hydrogen bonding and cation-π interactions. In addition, π-π interactions between berberine aromatic rings and two aromatic residues in the Smo transmembrane domain, Tyr394 and Phe484, were noted. Binding efficiency indices using an in silico approach to plot the Smo-specific binding potency of each ligand was performed. The mRNA level of Gli1 was studied as the outcome of Hh signalling pathway to show the effect of berberine on hedgehog signalling.
CONCLUSION: This study predicted the role of berberine as an inhibitor of Smo receptor, suggesting its effectiveness in hedgehog signalling during cancer treatment.

Matched MeSH terms: Hedgehog Proteins/metabolism*
Hedgehog signalling molecule, SMO is a poor prognostic marker in bladder cancer

Mohd Ariffin K, Abd Ghani F, Hussin H, Md Said S, Yunus R, Veerakumarasivam A, et al.

Malays J Pathol, 2021 Apr;43(1):49-54.
PMID: 33903305

INTRODUCTION: Hedgehog (HH) pathway is an important signalling cascade for growth and patterning during embryonic development. Constitutive activation of Hedgehog pathway can be found in various types of malignancies including medulloblastoma, basal cell carcinoma, gastrointestinal, breast, pancreatic, prostate cancer and leukaemia. Little is known about the expression and role of Hedgehog signalling in bladder cancer.
MATERIALS AND METHODS: The purpose of this study was to investigate the immunohistochemical expression of SMO in 112 bladder cancer cases and determine their association with demographic and clinicopathological parameters. Bladder cancer tissues were obtained from the Hospital Kuala Lumpur.
RESULTS: SMO was expressed in the cytoplasm of all cases of bladder cancer. 6 cases (5.4%) showed low expression, while 106 cases (94.6%) showed high expression. Positive expression of SMO protein was correlated with a few variables which include grade and stage of tumour, lymph node metastasis and distant metastasis. SMO expression showed statistically significant association with higher grade (p=0.001) and higher stage (p=0.042) of bladder cancer. SMO expression also showed borderline association with lymph node metastasis (p=0.056).
CONCLUSION: These findings indicate that SMO expression may be a poor prognostic marker in bladder cancer.

Matched MeSH terms: Hedgehog Proteins
The crosstalk of hedgehog, PI3K and Wnt pathways in diabetes

Benchoula K, Parhar IS, Wong EH

Arch Biochem Biophys, 2021 Feb 15;698:108743.
PMID: 33382998 DOI: 10.1016/j.abb.2020.108743

Hyperglycaemia causes pancreatic β-cells to release insulin that then attaches to a specific expression of receptor isoform and reverses high glucose concentrations. It is well known that insulin is capable of initiating insulin-receptor substrate (IRS)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling pathways in target cells; such as liver, adipose tissues, and muscles. However, recent discoveries indicate that many other pathways, such as the Hedgehog (Hh) and growth factor-stimulating Wingless-related integration (Wnt) signaling pathways; are activated in hyperglycaemia as well. Although these two pathways are traditionally thought to have a decisive role in cellular growth and differentiation only, recent reports show that they are involved in regulating cellular homeostasis and energy balance. While insulin-activated IRS/PI3K/PKB pathway cascades are primarily known to reduce glucose production, it was recently discovered to increase the Hh signaling pathway's stability, thereby activating the PI3K/PKB/mammalian target of rapamycin complex 2 (mTORC2) signaling pathway. The Hh signaling pathway not only plays a role in lipid metabolism, insulin sensitivity, inflammatory response, diabetes-related complications, but crosstalks with the Wnt signaling pathway resulting in improved insulin sensitivity and decrease inflammatory response in diabetes.

Matched MeSH terms: Hedgehog Proteins
Fulltext Patched-1 and smoothened, a hedgehog receptor and signal transducer are highly expressed in diffuse large B-cell lymphoma

Siti Nur Lina Azman, Huzlinda Hussin, Salmiah Md Said, Zanariah Alias, Maizaton Atmadini Abdullah

Malaysian Journal of Medicine and Health Sciences, 2017;13(2):1-6.
MyJurnal

Introduction: The Hedgehog (Hh) signalling pathway is a developmental signalling pathway involved in normal mammalian developmental and homeostasis of adult renewable tissues. In most adult tissues, this pathway remains silent and previous studies have shown that constitutive activation of Hedgehog signalling pathway leads to various types of malignancies including medulloblastomas, basal cell carcinoma, gastrointestinal, breast and prostate cancer. The purpose of this study was to investigate the immunohistochemical expression of Hedgehog pathway proteins in Diffuse Large B-cell Lymphoma and determine their association with overall survival (OS). Methods: Positive control using normal tonsils were included in each batch of immunohistochemical staining procedure. Results: PTCH1 proteins were highly expressed in DLBCL and showed strong staining intensity in 107 (100%) cases and SMO proteins were expressed in 105 (98.1%) cases. PTCH1 proteins were localised in the nucleus of tumour cells, whereas SMO proteins were mainly localised in the cytoplasm of tumour cells. Positive expression of PTCH1 and SMO proteins and overall survival of DLBCL patients were correlated with age, gender, race and tumour location. There was no significant correlation between the expression of these two proteins with any of the parameters. PTCH1 expression showed significant association with SMO expression (P=0.03). Conclusions: Our findings suggest that high expression of both PTCH1 and SMO may be important in the pathogenesis of DLBCL. However, additional mechanisms that may contribute to the activation of HH signalling in DLBCL needs to be further explored.

Matched MeSH terms: Hedgehog Proteins