• Journal of Korean Neurosurgical Society
• /
• v.61 no.3
• /
• pp.292-301
• /
• 2018

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. Despite these recent advancements, identification of effective targeted therapies remains a challenge for several reasons. First, significant molecular heterogeneity exists within the four subgroups, meaning this classification system alone may not be sufficient to predict response to a particular therapy. Second, the majority of novel agents are currently tested at the time of recurrence, after which significant selective pressures have been exerted by radiation and chemotherapy. Recent studies demonstrate selection of tumor sub-clones that exhibit genetic divergence from the primary tumor, exist within metastatic and recurrent tumor populations. Therefore, tumor resampling at the time of recurrence may become necessary to accurately select patients for personalized therapy.

• BMB Reports
• /
• v.52 no.10
• /
• pp.619-624
• /
• 2019

The primary cilium is a microtubule-based structure projecting from a cell. Although the primary cilium shows no motility, it can recognize environmental stimuli. Thus, ciliary defects cause severe abnormalities called ciliopathies. Ciliogenesis is a very complex process and involves a myriad of components and regulators. In order to excavate the novel positive regulators of ciliogenesis, we performed mRNA microarray using starved NIH/3T3 cells. We selected 62 murine genes with corresponding human orthologs, with significantly upregulated expression at 24 h after serum withdrawal. Finally, calpain-6 was selected as a positive regulator of ciliogenesis. We found that calpain-6 deficiency reduced the percentage of ciliated cells and impaired sonic hedgehog signaling. It has been speculated that this defect might be associated with decreased levels of ${\alpha}-tubulin$ acetylation at lysine 40. This is the first study to report a novel role of calpain-6 in the formation of primary cilia.

• Molecules and Cells
• /
• v.41 no.3
• /
• pp.224-233
• /
• 2018

Primary cilia are solitary, non-motile, axonemal microtubule-based antenna-like organelles that project from the plasma membrane of most mammalian cells and are implicated in transducing hedgehog signals during development. It was recently proposed that aberrant SHH signaling may be implicated in the progression of idiopathic pulmonary fibrosis (IPF). However, the distribution and role of primary cilia in IPF remains unclear. Here, we clearly observed the primary cilia in alveolar epithelial cells, fibroblasts, and endothelial cells of human normal lung tissue. Then, we investigated the distribution of primary cilia in human IPF tissue samples using immunofluorescence. Tissues from six IPF cases showed an increase in the number of primary cilia in alveolar cells and fibroblasts. In addition, we observed an increase in ciliogenesis related genes such as IFT20 and IFT88 in IPF. Since major components of the SHH signaling pathway are known to be localized in primary cilia, we quantified the mRNA expression of the SHH signaling components using qRT-PCR in both IPF and control lung. mRNA levels of SHH, the coreceptor SMO, and the transcription factors GLI1 and GLI2 were upregulated in IPF compared with control. Furthermore, the nuclear localization of GLI1 was observed mainly in alveolar epithelia and fibroblasts. In addition, we showed that defective KIF3A-mediated ciliary loss in human type II alveolar epithelial cell lines leads to disruption of SHH signaling. These results indicate that a significant increase in the number of primary cilia in IPF contributes to the upregulation of SHH signals.

• The Journal of Korean Physical Therapy
• /
• v.13 no.2
• /
• pp.433-444
• /
• 2001

This review highlights the ontogenesis and the differentiation of motor neuron in spinal cord, and introduce the survival motor neuron(SMN) which is associated with growth and survival of motor neurons. The differentiation of floor plate cells and motor neurons in the vertebrate neural tube appears to be induced by signals from the notochord. This signal is Sonic hedgehog(Shh). The early development of motor neurons involves the inductive action of Shh. The SMN gene is essential for embryonic viability. SMN mRNA is also expressed in virtually all cell types in spinal cord, including large motor neurons. The SMN protein is involved in RNA processing and during early embryonic development is necessary fer cell survival. Two SMN genes are present in 5q 13 in humans: the telomeric gene(SMNt), which is the SMA-determining gene, and the centromeric analog gene(SMNc). The majority of transcripts from the SMNt gene are full length but, major transcripts of the SMNc gene have a high degrees of alternative splicing and tend to have little or no exon 7. The SMN is involved in the RNA processing(the biogenesis of snRNPs and pre-mRNA splicing), the anti-apoptotic effects, and regulating gene expression.

• Development and Reproduction
• /
• v.25 no.4
• /
• pp.279-291
• /
• 2021

Hair loss is one of the most common chronic diseases, with a detrimental effect on a patient's psychosocial life. Hair loss results from damage to the hair follicle (HF) and/or hair regeneration cycle. Various damaging factors, such as hereditary, inflammation, and aging, impair hair regeneration by inhibiting the activation of hair follicle stem cells (HFSCs) and dermal papilla cells (DPCs). Formyl peptide receptor 2 (FPR2) regulates the inflammatory response and the activity of various types of stem cells, and has recently been reported to have a protective effect on hair loss. Given that stem cell activity is the driving force for hair regeneration, we hypothesized that FPR2 influences hair regeneration by mediating HFSC activity. To prove this hypothesis, we investigated the role of FPR2 in hair regeneration using Fpr2 knockout (KO) mice. Fpr2 KO mice were found to have excessive hair loss and abnormal HF structures and skin layer construction compared to wild-type (WT) mice. The levels of Sonic hedgehog (Shh) and β-catenin, which promote HF regeneration, were significantly decreased, and the expression of bone morphogenetic protein (Bmp)2/4, an inhibitor of the anagen phase, was significantly increased in Fpr2 KO mice compared to WT mice. The proliferation of HFSCs and DPCs was significantly lower in Fpr2 KO mice than in WT mice. These findings demonstrate that FPR2 impacts signaling molecules that regulate HF regeneration, and is involved in the proliferation of HFSCs and DPCs, exerting a protective effect on hair loss.

• Molecules and Cells
• /
• v.42 no.9
• /
• pp.661-671
• /
• 2019

Adipose tissue-derived mesenchymal stem cells (ADSCs) are promising for regenerating degenerated intervertebral discs (IVDs), but the low efficiency of nucleus pulposus (NP)-specific differentiation limits their clinical applications. The Sonic hedgehog (Shh) signaling pathway is important in NP-specific differentiation of ADSCs, and Smoothened Agonist (SAG) is a highly specific and effective agonist of Shh signaling. In this study, we proposed a new differentiation strategy with the use of the small molecule SAG. The NP-specific differentiation and extracellular matrix (ECM) synthesis of ADSCs were measured in vitro, and the regenerative effects of SAG pretreated ADSCs in degenerated IVDs were verified in vivo. The results showed that the combination of SAG and transforming growth factor-${\beta}3$ ($TGF-{\beta}3$) is able to increase the ECM synthesis of ADSCs. In addition, the gene and protein expression levels of NP-specific markers were increased by treatment with SAG and $TGF-{\beta}3$. Furthermore, SAG pretreated ADSCs can also improve the disc height, water content, ECM content, and structure of degenerated IVDs in vivo. Our new differentiation scheme has high efficiency in inducing NP-specific differentiation of ADSCs and is promising for stem cell-based treatment of degenerated IVDs.

• Asian-Australasian Journal of Animal Sciences
• /
• v.32 no.3
• /
• pp.341-349
• /
• 2019

Objective: Internal organs indirectly affect economic performance and well-being of animals. Study of internal organs during later layer period will allow full utilization of layer hens. Hence, we conducted a genome-wide association study (GWAS) to identify potential quantitative trait loci or genes that potentially contribute to internal organ weight. Methods: A total of 1,512 chickens originating from White Leghorn and Dongxiang Blue-Shelled chickens were genotyped using high-density Affymetrix 600 K single nucleotide polymorphism (SNP) array. We conducted a GWAS, linkage disequilibrium analysis, and heritability estimated based on SNP information by using GEMMA, Haploview and GCTA software. Results: Our results displayed that internal organ weights show moderate to high (0.283 to 0.640) heritability. Variance partitioned across chromosomes and chromosome lengths had a linear relationship for liver weight and gizzard weight ($R^2=0.493$, 0.753). A total of 23 highly significant SNPs that associated with all internal organ weights were mainly located on Gallus gallus autosome (GGA) 1 and GGA4. Six SNPs on GGA2 affected heart weight. After the final analysis, five top SNPs were in or near genes 5-Hydroxytryptamine receptor 2A, general transcription factor IIF polypeptide 2, WD repeat and FYVE domain containing 2, non-SMC condensin I complex subunit G, and sonic hedgehog, which were considered as candidate genes having a pervasive role in internal organ weights. Conclusion: Our findings provide an understanding of the underlying genetic architecture of internal organs and are beneficial in the selection of chickens.

• Journal of Genetic Medicine
• /
• v.18 no.1
• /
• pp.64-69
• /
• 2021

Primary cilium has a signal transduction function that is essential for brain development, and also determines cell polarity and acts as a mediator for important signaling systems, especially the Sonic Hedgehog (SHH) pathway. TBC1D32 is a ciliary protein, implicated in SHH signaling. Biallelic mutations in the TBC1D32 gene causes a kind of ciliopathy, heterogeneous developmental or degenerative disorders that affect multiple organs, including the brain. Here we report a boy who carried compound heterozygous variants in TBC1D32. The patient showed hypotonia, respiratory difficulty, and multiple anomalies at his birth. He was diagnosed with congenital hypopituitarism and treated with T4, hydrocortisone, and growth hormone. Despite the hormonal replacement, the patient needed long-term respiratory support with tracheostomy and nutritional support with a feeding tube. His developmental milestones were severely retarded. Hydrocephalus and strabismus developed and both required surgery, during the outpatient follow-up. Whole-exome sequencing indicated compound heterozygous variants, c.2200C>T (p.Arg734^*) and c.156-1G>T, in TBC1D32 gene. This is the first Korean case of TBC1D32-related ciliopathy and we reported detailed and sequential clinical features. This case demonstrated the utility of whole-exome sequencing and provided valuable clinical data on ultra-rare disease.

• KSBB Journal
• /
• v.20 no.5 s.94
• /
• pp.363-370
• /
• 2005

Neural stem cells (NSCs) of the central nervous system (CNS) have raised a great interest not only for their importance in basic neural development but also for their therapeutic potentials in neurologically degenerative diseases such as Parkinson's, Alzheimer and stroke. During the CNS development, two molecular cascades determine specification of midbrain dopamine system. In one pathway, FGF-8, sonic hedgehog and transcription factor Nurr1 specify dopamine neurotransmitter phenotype. In the other, transcription factors $Lm{\times}lb\;and\;Pt{\times}3$ are required for induction of dopaminergic neurons. In Nurr1 knockout mouse, tyrosine hydroxylase (TH) positive cells fail to appear in substantia nigra, indicating that Nurr1 is essential in specification of dopaminergic cell phenotype. In this study, we used the immortalized human NSCs retrovirally transduced with Nurr1 gene to probe the Nurr1 mediated mechanism to induce dopamine phenotype. While Nurr1 over-expression alone did not generate dopamine phenotype in NSCs, applications of retinoid and forskolin induced expression of TH and AADC mRNAs. In addition, co-cultures of Nurr1 expressing NSCs with human astrocytes induced a marked increase of TH expression. In this co-culture system, the addition of retinoid and forskolin dramatically increased expression of TH. These results indicate that the immortalized human NSCs with Nurr1 gene could have a clinical utility for cell replacement for the Parkinson patients.

• Journal of Applied Biological Chemistry
• /
• v.64 no.4
• /
• pp.421-431
• /
• 2021

It has been suggested that some toothpastes have the potential to promote hair growth. However, there was no scientific verification on the hair growth effect of toothpaste and no scientific report on major active ingredients in toothpaste. In this work, toothpaste and its constituents were applied topically over the shaved skin of C57BL/6 mice and evaluated. Results indicated that toothpaste showed hair growth effect. Also, the effect of toothpaste constituents on the proliferation rate of keratinocyte cells was investigated. The mixture solution of 𝛼-tocopherol acetate, l-menthol, and stevioside, each of that was known to promote hair growth and other toothpaste constituents were applied topically on mouse skin. When the mixture solution was included, hair growth effect was observed in mice. Transcriptome analysis was performed using the dorsal epidermis of mice from the group treated with toothpaste, the mixture which are presumed to be active ingredients for hair growth, and from mice used for the control group. As a result of analyzing the genes whose expression was significantly changed in each treatment group, the gene patterns of the two groups were very similar. Also, when functional genomic analysis was performed, genes with functions related to hair growth regulation showed a high extent of the change in both groups. Hair growth-related genes whose expression was changed in both groups included keratin, keratin-related proteins, forkhead box, and sonic hedgehog. Therefore, the hair growth effect of toothpaste is thought to be due to the effect of a mixture of 𝛼-tocopherol acetate, l-menthol, and stevioside.