• Journal of Korean Neurosurgical Society
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• 제61권3호
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• pp.292-301
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• 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
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• 제52권10호
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• pp.619-624
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• 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
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• 제41권3호
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• pp.224-233
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• 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
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• 제13권2호
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• pp.433-444
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• 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.

• 한국발생생물학회지:발생과생식
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• 제25권4호
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• pp.279-291
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• 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
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• 제42권9호
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• pp.661-671
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• 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
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• 제32권3호
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• pp.341-349
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• 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
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• 제18권1호
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• pp.64-69
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• 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
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• 제20권5호
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• pp.363-370
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• 2005

중추신경계의 신경간세포가 파킨슨병과 뇌졸중과 같은 퇴행성 뇌 질환의 치료뿐만이 아니라 신경세포 발생과정에서의 중요성 때문에 최근에 커다란 관심의 대상이 되고 있다. 중추신경계의 발생과정 동안에, 중뇌의 도파민 신경세포의 형성은 두 가지의 분자생물학적인 기작에 의해서 결정된다. 첫째로, FGF-8, sonic hedgehog 그리고 전사조절인자 인 Nurr1이 도파민 신경세포의 형질을 결정짓는다. 또 다른 기작으로는, 전사조절인자 인 $Lm{\times}lb$와 $Pt{\times}3$가 중요하게 관련되어있다. 특히 Nurr1이 결핍된 생쥐에서, 타이로신수산화효소 (Tyrosine bydroxylase, TH) 면역양성 세포들이 중뇌흑색질에서 발견되지 않으므로 Nurr1이 도파민 신경세포의 발생에 필수적임을 알 수 있다. 본 연구에서는 도파민 신경세포의 형질을 유도하는데 있어서 Nurr1이 매개하는 기작을 연구하기 위해서 레트로 바이러스를 이용하여 Nurr1을 도입한 무한증식 신경간세포를 사용하였다. Nurr1 유전자의 과발현 만으로는 신경간세포에서 도파민 신경세포의 형질을 유도하지는 못하지만, 레티노이드 (retinoid, RA)와 폴스콜린 (forskolin, FK)을 처리하여 TH와 방향성 L-아미노산 탈카르복시화효소 (aromatic L-amino acid decarboxylase, AADC) mRNA의 발현을 유도하였다. 또한, Nurr1 과발현 신경간세포를 사람 별아교세포와 공동배양 하여 TH 발현량을 많이 증가시켰다. 이러한 공동배양실험에서, RA와 FK를 처리하면 TH의 발현수준이 더욱 더 증가함을 발견하였다. 이러한 결과들은 Nurr1 유전자를 도입한 사람 신경간세포가 파킨슨병 환자들에게 세포이식을 통한 유전자 치료의 유용성을 시사하고 있다.

• Journal of Applied Biological Chemistry
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• 제64권4호
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• pp.421-431
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• 2021

예전부터 치약이 모발성장을 촉진시킬 수 있는 잠재력을 갖고 있다고 제안되어 왔지만 발모효과에 대한 과학적 검증과 치약 내 주요 활성성분에 대한 연구는 보고된 바가 없다. 따라서 본 연구에서는 치약을 이용하여 피부 각질세포의 성장 및 C57BL/6 마우스의 제모된 등쪽 피부에 국소적으로 적용하여 모발의 성장 촉진 여부를 평가하였다. 본 연구 결과 치약의 구성 성분으로서 문헌에서 발모 효과가 있다고 알려진 𝛼-tocopherol acetate와 l-menthol, stevioside 혼합액과, 이들을 제외한 치약 조성 성분들의 혼합액을 각각 두 그룹의 C57BL/6 마우스의 제모된 피부에 국소적으로 적용한 경우, 치약 성분의 혼합액은 발모효과를 보이지 않았고, 𝛼-tocopherol acetate과 l-menthol, stevioside 혼합액이 포함되었을 경우에는 마우스에서 발모 효과가 나타났다. 따라서, 치약을 구성하는 보조성분들인 α-tocopherol acetate과 l-menthol, stevioside 혼합물은 in vivo에서의 모발성장에 있어 잠재력을 갖고 있음을 확인하였다. 또한 치약을 처리한 그룹의 마우스와 발모 유효 성분으로 추정되는 𝛼-tocopherol acetate과 l-menthol, stevioside를 혼합 처리한 그룹의 마우스, 그리고 대조군의 마우스의 등쪽 표피를 취하여 전사체 분석을 진행한 결과 대조군에 비해서 각각의 처리군에서 유의적으로 발현된 유전자 패턴은 매우 유사함을 보였다. 또한 기능유전체적 분석을 하였을 때, 두 그룹에서 공통적으로 발모 조절 관련 기능의 유전자들이 매우 큰 비율의 변화를 보였다. 두 그룹에서 발현이 변화한 발모관련 유전자들로는 케라틴과 케라틴 관련 단백질, forkhead box, sonic hedgehog 등이 관찰되었다. 따라서, 치약의 발모 효과는 𝛼-tocopherol acetate과 l-menthol, stevioside 혼합물의 효과에 기인하는 것으로 생각된다.