RESUMO
Pathogenic AGO1 variants have been associated with neurodevelopmental disorders, including autism spectrum disorder, developmental delay, intellectual disability, and dysmorphic facial appearance. In mammalian models, defects in microRNA (miRNA) biogenesis are associated with congenital heart disease and dilated cardiomyopathy. We describe the case of a patient with partial anomalous pulmonary venous return, hypoplastic left lung, bilateral pulmonary sequestration, and dilated myocardiopathy. We identified a de novo pathogenic variant of AGO1, which encodes an Argonaute protein forming a gene-silencing complex with microRNAs. The patient was diagnosed with dilated cardiomyopathy with no apparent cause at 3 years of age. She was started on enalapril and carvedilol, and her heart failure was well controlled. We expanded the AGO1-associated phenotype to include complex congenital cardiovascular anomaly and dilated cardiomyopathy in humans.
Assuntos
Transtorno do Espectro Autista , Cardiomiopatia Dilatada , Deficiência Intelectual , MicroRNAs , Transtornos do Neurodesenvolvimento , Humanos , Feminino , Animais , Transtorno do Espectro Autista/genética , MicroRNAs/genética , Deficiência Intelectual/genética , Mamíferos/genética , Mamíferos/metabolismoRESUMO
Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) and genitopatellar syndrome (GPS) are caused by variants of lysine acetyltransferase 6B (KAT6B). These variants tend to occur in the terminal exons of KAT6B. Here, we report a patient with global developmental delay, intellectual disability, autistic behavior, muscular hypotonia, facial dysmorphism, and seizures caused by a novel missense variant in exon 7 of KAT6B. The patient showed a phenotype differing from those of SBBYSS and GPS. We also report patients with missense variants in the proximal exons of KAT6B showing dysmorphic features and autistic behavior not resembling the characteristics of SBBYSS and GPS. Missense variants in the proximal exons of KAT6B may have a dominant negative effect or cause gain of function, leading to unique phenotypes not resembling those of SBBYSS and GPS.
RESUMO
Pituitary endocrine cells are supplied by Sox2-expressing stem/progenitor cells in the anterior lobe of the adult pituitary gland. These SOX2-positive cells are maintained in two types of microenvironments (niches): the marginal cell layer (MCL)-niche and the parenchymal-niche. Recently, we isolated dense SOX2-positive cell clusters from the parenchymal-niche by taking advantage of their resistance to protease treatment as parenchymal stem/progenitor cell (PS)-clusters. In the present study, by analyzing these isolated PS-clusters, we attempted to identify novel structural characteristics of pituitary stem/progenitor cell niches. Quantitative real-time PCR showed that tight junction-related genes were distinctly expressed in the isolated PS-clusters. Immunocytostaining showed that the tight junction molecules, ZO-1 and occludin, were localized in the apical membrane facing the pseudo-follicle-like structure of the isolated PS-clusters regardless of the expression of S100ß, which distinguishes the sub-population of SOX2-positive cells. Furthermore, immunohistochemistry of the pituitary glands of adult rats clearly demonstrated that ZO-1 and occludin were densely present in the parenchymal-niche encircling the pseudo-follicle, while they were observed in the apical membrane in the MCL-niche facing the residual lumen. Collectively, these tight junction-related proteins might be involved in the architecture and maintenance of the plasticity of pituitary stem/progenitor cell niches.
Assuntos
Proteínas de Junções Íntimas , Junções Íntimas , Animais , Ocludina/genética , Ocludina/metabolismo , Hipófise/metabolismo , Ratos , Nicho de Células-Tronco , Células-Tronco , Proteínas de Junções Íntimas/genética , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/metabolismoRESUMO
Okur-Chung neurodevelopmental syndrome is a rare autosomal dominant disorder caused by pathogenic variants in CSNK2A1, which encodes the alpha 1 catalytic subunit of -casein kinase II. This syndrome is characterized by intellectual disability, developmental delay, and multisystemic -abnormalities including those of the brain, extremities, and skin as well as cardiovascular, gastrointestinal, and immune systems. In this study, we describe a 5-year-old boy with a de novo novel nonsense variant in CSNK2A1, NM_001895.3:c.319C>T (p.Arg107*). He showed bilateral persistent hyperplastic primary vitreous with microphthalmia, lens dysplasia, and coloboma. Ocular manifestations are very rare in this syndrome, and this study expands the spectrum of the clinical presentations of this syndrome.
RESUMO
Variants of GRIN1, which encodes GluN1, are associated with developmental delay, epilepsy, and cortical malformation. Here, we report a case of arthrogryposis multiplex congenita with polymicrogyria and infantile encephalopathy caused by a heterozygous variant, c.1949A>C, p.(Asn650Thr) of GRIN1, which could result in the disruption of the third transmembrane domain (M3) of GluN1. This case expands our understanding of the known phenotypes of GRIN1-related neurodevelopmental disorders.
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Kabuki syndrome is characterized by a variable degree of intellectual disability, characteristic facial features, and complications in various organs. Many variants have been identified in two causative genes, that is, lysine methyltransferase 2D (KMT2D) and lysine demethylase 6A (KDM6A). In this study, we present the results of genetic screening of 100 patients with a suspected diagnosis of Kabuki syndrome in our center from July 2010 to June 2018. We identified 76 variants (43 novel) in KMT2D and 4 variants (3 novel) in KDM6A as pathogenic or likely pathogenic. Rare variants included a deep splicing variant (c.14000-8C>G) confirmed by RNA sequencing and an 18% mosaicism level for a KMT2D mutation. We also characterized a case with a blended phenotype consisting of Kabuki syndrome, osteogenesis imperfecta, and 16p13.11 microdeletion. We summarized the clinical phenotypes of 44 patients including a patient who developed cervical cancer of unknown origin at 16 years of age. This study presents important details of patients with Kabuki syndrome including rare clinical cases and expands our genetic understanding of this syndrome, which will help clinicians and researchers better manage and understand patients with Kabuki syndrome they may encounter.
Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Face/anormalidades , Predisposição Genética para Doença , Doenças Hematológicas/genética , Histona Desmetilases/genética , Proteínas de Neoplasias/genética , Neoplasias do Colo do Útero/genética , Doenças Vestibulares/genética , Anormalidades Múltiplas/epidemiologia , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Face/patologia , Feminino , Heterogeneidade Genética , Testes Genéticos/métodos , Genótipo , Doenças Hematológicas/complicações , Doenças Hematológicas/epidemiologia , Doenças Hematológicas/patologia , Humanos , Masculino , Mutação , Fenótipo , Neoplasias do Colo do Útero/complicações , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/patologia , Doenças Vestibulares/complicações , Doenças Vestibulares/epidemiologia , Doenças Vestibulares/patologia , Adulto JovemRESUMO
OBJECTIVE: COL4A1 variant causes severe central nervous system (CNS) anomalies, including hydranencephaly. However, the pathogenic mechanism underlying the COL4A1 phenotype remains unclear. Here, we report de novo COL4A1 variants in four Japanese patients with typical or rare CNS involvement and exhibiting diverse phenotypes. METHODS: We identified and enrolled four patients with white matter abnormalities and cerebral structural defects suggestive of cerebrovascular disease. Genetic analysis was performed using panel sequencing. RESULTS: All the patients were perinatally asymptomatic during the infantile period but exhibited developmental delay and growth retardation later. All the patients exhibited CNS symptoms, including psychomotor disability, spastic paralysis, and epilepsy. Brain magnetic resonance imaging revealed hydranencephaly (n = 1), ventriculomegaly (n = 4) associated with cerebral hemorrhage, and atretic encephalocele (n = 1). Three patients had developed congenital cataract, while two had hematuria. We identified two COL4A1 missense variants [exon32:c.2555G > A p.(Gly852Asp), exon40:c.3407G > A p.(Gly1136Asp)] and two in frame variants [exon32:c.2603_2609delinsATCCTGA p.(Ala868_Gly870delinsAspProGlu), exon36:c.3054delinsTGTAGAT p.(Leu1018delinsPheValAsp)]. The in frame variants were associated with severe CNS anomalies, hydranencephaly, and severe ventriculomegaly. Atretic encephalocele has never been reported in individuals with COL4A1 variants. CONCLUSIONS: Our findings suggest that COL4A1 variants cause variable CNS symptoms. Association between clinical phenotypes and each COL4A1 variant would clarify their underlying etiologies.
Assuntos
Colágeno Tipo IV/metabolismo , Adolescente , Doenças do Sistema Nervoso Central/genética , Doenças do Sistema Nervoso Central/fisiopatologia , Hemorragia Cerebral/genética , Transtornos Cerebrovasculares/genética , Transtornos Cerebrovasculares/fisiopatologia , Colágeno Tipo IV/genética , Colágeno Tipo IV/fisiologia , Epilepsia/genética , Humanos , Lactente , Japão , Masculino , Mutação de Sentido Incorreto/genética , Linhagem , FenótipoRESUMO
Primrose syndrome (OMIM 259050) is a rare disorder characterised by macrocephaly with developmental delay, a recognisable facial phenotype, altered glucose metabolism, and other features such as sensorineural hearing loss, short stature, and calcification of the ear cartilage. It is caused by heterozygous variants in ZBTB20, a member of the POK family of transcription repressors. Recently, this gene was shown to have a role in skeletal development through its action on chondrocyte differentiation by repression of SOX9. We describe five unrelated patients with Primrose syndrome and distinct skeletal features including multiple Wormian bones, platybasia, bitemporal bossing, bathrocephaly, slender bones, epiphyseal and spondylar dysplasia. The radiological abnormalities of the skull and the epiphyseal dysplasia were the most consistent findings. This novel constellation of skeletal features expands the phenotypic spectrum of the disorder.
Assuntos
Anormalidades Múltiplas/patologia , Osso e Ossos/anormalidades , Calcinose/patologia , Otopatias/patologia , Deficiência Intelectual/patologia , Atrofia Muscular/patologia , Fenótipo , Anormalidades Múltiplas/genética , Adolescente , Osso e Ossos/diagnóstico por imagem , Calcinose/genética , Criança , Pré-Escolar , Otopatias/genética , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Atrofia Muscular/genética , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição/genética , Adulto JovemAssuntos
Cromossomos Humanos Par 9 , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/genética , Craniossinostoses/diagnóstico , Craniossinostoses/genética , Homozigoto , Subunidade alfa de Receptor de Interleucina-11/genética , Dissomia Uniparental , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Feminino , Genômica/métodos , Humanos , Lactente , Herança Materna , Fenótipo , Tomografia Computadorizada EspiralRESUMO
Infection with human herpes virus 1 (HHV1) is a suspected cause of human male infertility. However, the correlation between HHV1 infection and infertility is still unclear. We have previously generated transgenic rats that ectopically express the HHV1 thymidine kinase gene (HHV1-TK) in post-meiotic spermatids and found they had aberrant spermatogenesis and infertility. Therefore, we hypothesized that human infertility might be caused by HHV1 infection. Here, we examined whether HHV1-TK is expressed in human testis by analyzing the presence of its transcript and protein. Specimens were collected by biopsy from 30 azoospermic infertile male patients. RT-PCR and immunohistochemistry showed that 23 patients were positive for HHV1-TK expression, while seven patients were negative. Thus, we demonstrated HHV1-TK expression, indicating HHV1 infection, in the testis of human azoospermic infertile males for the first time; our findings represent a great advancement toward the verification of our hypothesis that HHV1-TK expression might cause human infertility.
Assuntos
Herpes Simples/virologia , Herpesvirus Humano 1 , Infertilidade Masculina/virologia , Testículo/virologia , Timidina Quinase/fisiologia , Proteínas Virais/fisiologia , Adulto , Humanos , MasculinoRESUMO
Pituitary endocrine cells are supplied by Sox2-expressing stem/progenitor cells in the anterior lobe of the adult pituitary. In relation to their microenvironment ("niche"), SOX2-positive cells exist in two types of niches; the marginal cell layer-niche and the parenchymal-niche. Recently, we isolated dense stem/progenitor cell clusters from the parenchymal-niche as parenchymal stem/progenitor cell (PS)-clusters. We classified these PS-clusters into three subtypes based on differences in S100ß-expression (S100ß-positive, -negative, and -mixed type), and reported that S100ß-positive PS-clusters exhibited the capacity for differentiation into endocrine cells under 3-dimensional cultivation system. In the present study, we further characterized S100ß-positive PS-clusters using an in vitro 2-dimensional cultivation system. The results demonstrated that S100ß-positive PS-clusters in the 2-dimensional cultivation system proliferated more actively than S100ß-negative clusters. Moreover, in 2-dimensional cultivation conditions, S100ß-positive PS-clusters showed differentiation capacity into non-endocrine cells (Myogenin-, αSMA-, NG2-, or SOX17-positive cells) but not into endocrine cells, whereas S100ß-negative PS-clusters did not. Collectively, PS-clusters were heterogeneous, exhibiting different proliferation and differentiation properties based on the difference in S100ß-expression. Specifically, a part of SOX2-positive cells in the parenchymal-niche had capacities for differentiation into non-endocrine cells, and S100ß-positive PS-clusters may be in more progressive stages toward differentiation than S100ß-negative clusters.
Assuntos
Células-Tronco Adultas/citologia , Técnicas de Cultura de Células/métodos , Adeno-Hipófise/citologia , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Células-Tronco Adultas/metabolismo , Animais , Biomarcadores/metabolismo , Diferenciação Celular , Plasticidade Celular , Proliferação de Células , Células Cultivadas , Células Endócrinas/citologia , Células Endócrinas/metabolismo , Adeno-Hipófise/metabolismo , Ratos , Subunidade beta da Proteína Ligante de Cálcio S100/genética , Fatores de Transcrição SOXB1/metabolismo , Nicho de Células-TroncoRESUMO
The published online version contains mistake in Table 1, Table 2, and some data in Materials and Methods.
RESUMO
In the pituitary gland, S100ß-positive cells localize in the neurohypophysis and adenohypophysis but the lineage of the two groups remains obscure. S100ß is often observed in many neural crest-derived cell types. Therefore, in this study, we investigate the origin of pituitary S100ß-positive cells by immunohistochemistry for SOX10, a potent neural crest cell marker, using S100ß-green fluorescence protein-transgenic rats. On embryonic day 21.5, a SOX10-positive cell population, which was also positive for the stem/progenitor cell marker SOX2, emerged in the pituitary stalk and posterior lobe and subsequently expanded to create a rostral-caudal gradient on postnatal day 3 (P3). Thereafter, SOX10-positive cells appeared in the intermediate lobe by P15, localizing to the boundary facing the posterior lobe, the gap between the lobule structures and the marginal cell layer, a pituitary stem/progenitor cell niche. Subsequently, there was an increase in SOX10/S100ß double-positive cells; some of these cells in the gap between the lobule structures showed extended cytoplasm containing F-actin, indicating a feature of migration activity. The proportion of SOX10-positive cells in the postnatal anterior lobe was lower than 0.025% but about half of them co-localized with the pituitary-specific progenitor cell marker PROP1. Collectively, the present study identified that one of the lineages of S100ß-positive cells is a SOX10-positive one and that SOX10-positive cells express pituitary stem/progenitor cell marker genes.
Assuntos
Desenvolvimento Embrionário , Hipófise/embriologia , Hipófise/metabolismo , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Fatores de Transcrição SOXE/metabolismo , Animais , Animais Recém-Nascidos , Movimento Celular , Proliferação de Células , Embrião de Mamíferos/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Hipófise/citologia , Adeno-Hipófise/citologia , Adeno-Hipófise/metabolismo , Ratos Wistar , Fatores de Transcrição SOXB1/metabolismoRESUMO
The published online version contains mistakes in Table 1, Table 2 and Fig. 2. See below for the corrected Tables and Figure.
RESUMO
The gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), are important hormones in vertebrate reproduction. The isolation of gonadotropins from the pituitary gland is sub-optimal, as the cross-contamination of one hormone with another is common and often results in the variation in the measured activity of LH and FSH. The production of recombinant hormones is, therefore, a viable approach to solve this problem. This study aimed to express recombinant rat, mouse, and mastomys FSH and LH in Chinese hamster ovary (CHO) cells. Their common α-subunits along with their hormone-specific ß-subunits were encoded in a single mammalian expression vector. FSH from all three species was expressed, whereas expression was achieved only for the mouse LH. Immunohistochemistry for rat alpha subunit of glycoprotein hormone (αGSU) and LHß and FSHß subunits confirmed the production of the dimeric hormone in CHO cells. The recombinant rodent gonadotropins were confirmed to be biologically active; estradiol production was increased by recombinant FSH in granulosa cells, while recombinant LH increased testosterone production in Leydig cells.
Assuntos
Hormônio Foliculoestimulante/biossíntese , Vetores Genéticos , Hormônio Luteinizante/biossíntese , Animais , Células CHO , Cricetulus , Hormônio Foliculoestimulante/genética , Hormônio Luteinizante/genética , Masculino , Camundongos Endogâmicos C57BL , Murinae , Ratos Wistar , Proteínas Recombinantes/biossínteseRESUMO
Sox2-expressing stem/progenitor cells in the anterior lobe of the pituitary gland form two types of micro-environments (niches): the marginal cell layer and dense cell clusters in the parenchyma. In relation to the mechanism of regulation of niches, juxtacrine signaling via ephrin and its receptor Eph is known to play important roles in various niches. The ephrin and Eph families are divided into two subclasses to create ephrin/Eph signaling in co-operation with confined partners. Recently, we reported that ephrin-B2 localizes specifically to both pituitary niches. However, the Ephs interacting with ephrin-B2 in these pituitary niches have not yet been identified. Therefore, the present study aims to identify the Ephs interacting with ephrin-B2 and the cells that produce them in the rat pituitary gland. In situ hybridization and immunohistochemistry demonstrated cell type-specific localization of candidate interacting partners for ephrin-B2, including EphA4 in cells located in the posterior lobe, EphB1 in gonadotropes, EphB2 in corticotropes, EphB3 in stem/progenitor cells and EphB4 in endothelial cells in the adult pituitary gland. In particular, double-immunohistochemistry showed cis-interactions between EphB3 and ephrin-B2 in the apical cell membranes of stem/progenitor cell niches throughout life and trans-interactions between EphB2 produced by corticotropes and ephrin-B2 located in the basolateral cell membranes of stem/progenitor cells in the early postnatal pituitary gland. These data indicate that ephrin-B2 plays a role in pituitary stem/progenitor cell niches by selective interaction with EphB3 in cis and EphB2 in trans.
Assuntos
Efrina-B2/metabolismo , Hipófise/metabolismo , Ratos/metabolismo , Receptores da Família Eph/metabolismo , Animais , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Efrina-B2/análise , Hipófise/citologia , Hipófise/crescimento & desenvolvimento , Hipófise/ultraestrutura , Mapas de Interação de Proteínas , Ratos/crescimento & desenvolvimento , Ratos Wistar , Receptor EphB3/análise , Receptor EphB3/metabolismo , Receptores da Família Eph/análise , Células-Tronco/citologia , Células-Tronco/metabolismoRESUMO
The adenohypophysis comprises six types of endocrine cells, including PIT1-lineage cells such as growth hormone (GH)-producing cells and heterogeneous non-endocrine cells, such as pituitary stem/progenitor cells as a source of endocrine cells. We determine the expression of characteristic stem cell marker genes, including sex-determining region Y-box 2 (Sox2), in mouse pituitary-derived non-endocrine cell lines Tpit/E, Tpit/F1 and TtT/GF. We observed high expression of fibroblast growth factor (FGF) receptors in Tpit/F1 cells, which we characterised by cultivation in medium containing a basic FGF and B27 supplement as used for neural stem-cell differentiation. A 4-day cultivation of Tpit/F1 produced floating embryonic stem-cell-like clumps accompanied by a three-fold increase in Sox2 expression. Passages in these clumps maintained the proliferative activity and Sox2 expression levels. After 10 days of cultivation, Tpit/F1 cell clumps were immuno-positive for SOX2 and Ki67 (proliferation marker) and loosely attached to the well bottom. An additional 10 days of cultivation induced the emergence of GH-positive/pituitary-specific transcription factor (PIT1)-negative cells showing migration from the clumps. Pit1 overexpression in attached cells could not induce GH production. Finally, we confirmed the presence of PIT1-negative GH-producing cells (3.2-7.7 % of all GH-positive cells) in rat pituitary. Thus, we demonstrate that Tpit/F1 has the plasticity to differentiate into one type of hormone-producing cell.
Assuntos
Diferenciação Celular , Células Endócrinas/citologia , Hormônio do Crescimento/biossíntese , Hipófise/citologia , Animais , Biomarcadores/metabolismo , Adesão Celular , Agregação Celular , Linhagem Celular , Movimento Celular , Proliferação de Células , Forma Celular , Cromograninas/metabolismo , Meios de Cultura , Células Endócrinas/metabolismo , Regulação da Expressão Gênica , Camundongos , Ratos , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Fatores de Transcrição/metabolismoRESUMO
PROP1 is a pituitary specific transcription factor that plays a crucial role in pituitary organogenesis. The Prop1 shows varied expression patterns that promptly emerge and then fade during the early embryonic period. However, the regulatory mechanisms governing Prop1 expression remain unclear. Here, we investigated whether Prop1 was under epigenetic regulation by DNA methylation. Bisulfite sequencing was performed on DNA obtained from the pituitary glands and livers of rats on embryonic days (E) 13.5 and E14.5, and postnatal days (P) 4 and P30. The methylation of CpG sites in seven regions from 3-kb upstream of the Prop1 transcription start site through to its second intron were examined. Certain differences in CpG-methylation levels were observed in Region-1 (-2772 b to -2355 b), Region-4 (-198 b to +286 b), Region-5 (+671 b to +990 b), and Region-6 (+1113 b to +1273 b) based on comparisons between pituitary and liver DNA on E13.5. DNA methylation in pituitary glands on E14.5, P4, and P30 was generally similar to that observed in in the pituitary gland on E13.5, whereas the anterior and intermediate lobes of the pituitary gland on P4 and P30 showed only small differences. These results indicate that Prop1 is under regulation by CpG methylation during the early period of pituitary primordium development around E13.5.
Assuntos
Metilação de DNA , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/metabolismo , Hipófise/embriologia , Hipófise/fisiologia , Animais , Biologia Computacional , Ilhas de CpG , DNA/metabolismo , Epigênese Genética , Feminino , Perfilação da Expressão Gênica , Fígado/metabolismo , Masculino , Ratos , Ratos Wistar , TemperaturaRESUMO
Recent studies have demonstrated that Sox2-expressing stem/progenitor cells play roles in the pituitary cell turnover. Two types of niches have been proposed for stem/progenitor cells, the marginal cell layer (MCL) and the dense cell clusters in the parenchyma. Among them, the appearance of the parenchymal-niche only after birth indicates that this niche is involved in the cell turnover required for the postnatal pituitary. However, little is known about the roles of the parenchymal-niche and its regulation. The present study aimed to isolate pituitary stem/progenitor cells from the parenchymal-niche in the adult rat pituitary. Cell dispersion by stepwise treatment with proteases allowed the isolation of dense cell clusters. Immunocytochemistry demonstrated that clusters are universally composed of SOX2-positive cells, and most of them are positive for PROP1. Taken together with the anatomical analysis, we concluded that the isolated clusters are the parenchymal stem/progenitor cell (PS)-clusters, not the MCL-one. PS-clusters cultivated by serum-free overlay 3-dimensional culture maintained their stemness, and treatment with bFGF and EGF induced cyst-formation. Moreover, PS-clusters demonstrated some differentiation capacity with GSK3ß-inhibitor treatment. Collectively, the present study demonstrates a simple method for isolating stem/progenitor cells from the parenchymal-niche, and provides tools to analyze the factors for regulating the pituitary niches.