The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Yukio Kato - One of the best experts on this subject based on the ideXlab platform.
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retinoic acid signalling is a candidate regulator of the expression of pituitary specific transcription factor PROP1 in the developing rodent pituitary
Journal of Neuroendocrinology, 2018Co-Authors: Saishu Yoshida, Takako Kato, Hiroto Nishihara, Ken Fujiwara, Takashi Yashiro, Yukio KatoAbstract:Development of the anterior pituitary proceeds via spatiotemporal patterning of transcription factors and signalling molecules. Among them, retinoic acid (RA) functions as an important signalling molecule for vertebrate organogenesis in many tissues. However, little is known regarding the target genes in the developing pituitary. The present study aimed to clarify the relationship between endogenous RA signalling and mRNA expression of the pituitary-specific transcription factor PROP1 in the pituitary primordium of Rathke's pouch. Gene expression analysis and in situ hybridisation demonstrated that retinaldehyde dehydrogenases (Raldhs) and all types of RA receptors (Rars) are expressed at the level of transcription in the rat Rathke's pouch. Ex vivo organ culture using Rathke's pouch and an in vitro reporter assay demonstrated that RA signalling increases the expression level of PROP1 via RARα. Moreover, a reporter assay using serial truncated constructs of the 5'-upstream region of mouse PROP1 revealed a predicted cis-regulatory element of RARα. This is the first report of a relationship between RA signalling and PROP1-expression during early pituitary development.
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Involvement of DNA methylation in regulating rat PROP1 gene expression during pituitary organogenesis.
The Journal of reproduction and development, 2016Co-Authors: Hiroto Nishihara, Takako Kato, Saishu Yoshida, Naoto Nishimura, Hiroki Ueharu, Naoko Kanno, Jun Ohgane, Yukio KatoAbstract: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.
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Search for regulatory factors of the pituitary-specific transcription factor PROP1 gene.
The Journal of reproduction and development, 2015Co-Authors: Naoto Nishimura, Takako Kato, Saishu Yoshida, Hiroki Ueharu, Hiroto Nishihara, Shiori Shibuya, Masashi Higuchi, Naoko Kanno, Kotaro Horiguchi, Yukio KatoAbstract:Pituitary-specific transcription factor PROP1, a factor important for pituitary organogenesis, appears on rat embryonic day 11.5 (E11.5) in SOX2-expressing stem/progenitor cells and always coexists with SOX2 throughout life. PROP1-positive cells at one point occupy all cells in Rathke's pouch, followed by a rapid decrease in their number. Their regulatory factors, except for RBP-J, have not yet been clarified. This study aimed to use the 3 kb upstream region and 1st intron of mouse PROP1 to pinpoint a group of factors selected on the basis of expression in the early pituitary gland for expression of PROP1. Reporter assays for SOX2 and RBP-J showed that the stem/progenitor marker SOX2 has cell type-dependent inhibitory and activating functions through the proximal and distal upstream regions of PROP1, respectively, while RBP-J had small regulatory activity in some cell lines. Reporter assays for another 39 factors using the 3 kb upstream regions in CHO cells ultimately revealed that 8 factors, MSX2, PAX6, PIT1, PITX1, PITX2, RPF1, SOX8 and SOX11, but not RBP-J, regulate PROP1 expression. Furthermore, a synergy effect with SOX2 was observed for an additional 10 factors, FOXJ1, HES1, HEY1, HEY2, KLF6, MSX1, RUNX1, TEAD2, YBX2 and ZFP36Ll, which did not show substantial independent action. Thus, we demonstrated 19 candidates, including SOX2, to be regulatory factors of PROP1 expression.
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Three-dimensional studies of PROP1-expressing cells in the rat pituitary just before birth
Cell and tissue research, 2013Co-Authors: Hideji Yako, Takako Kato, Saishu Yoshida, Hiroki Ueharu, Masashi Higuchi, Naoko Kanno, Mo Chen, Yukio KatoAbstract:Recently, we demonstrated that differentiation was underway as early as embryonic day (E) 13.5 in the lateral region of the rat pituitary primordium. In this study, we analyze the heterogeneous property of cells in the pituitary at E21.5 (just before birth) leading to its biological function with the differentiation and expansion of tissue. The three-dimensional structure of the pituitary at E21.5 was built up from measurements taken from many DAPI-stained sections and cell populations positive to the stem/progenitor marker SOX2, pituitary-specific transcription factor PROP1 and paired-related homeodomain transcription factor PRX. At E21.5, the pituitary, composed of anterior and intermediate lobes, showed a flattened chestnut shape with dimensions of about 500 μm (dorsoventral axis) by 2500 μm (left-right axis) by 850 μm (rostrocaudal axis) and consisted in approximately 113,500, 16,000 and 14,800 cells in the anterior, intermediate and posterior lobes, respectively. Five cell types were observed expressing Sox2, PROP1 and Prx; these were heterogeneously distributed in the mediolateral and dorsoventral axes. In the anterior lobe, the marginal cell layer (MCL) was mostly occupied by stem/progenitor cells positive for SOX2, with the co-expression of PROP1 and/or Prx, whereas more SOX2-single-positive cells than those for PROP1 and PRX were scattered in the parenchyma. PRX-positive cells of mesenchymal origin invaded the parenchyma, together with PECAM- and NESTIN-positive cells, indicating the advance of vasculogenesis. Thus, marked developmental progress occurs regarding the transition of stem/progenitor cells in the MCL and regarding vasculogenesis in the parenchyma during the prenatal pituitary growth wave.
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significant quantitative and qualitative transition in pituitary stem progenitor cells occurs during the postnatal development of the rat anterior pituitary
Journal of Neuroendocrinology, 2011Co-Authors: Saishu Yoshida, Takao Susa, Takako Kato, Hideji Yako, L Y Cai, M Osuna, Kinji Inoue, Yukio KatoAbstract:We reported recently that a pituitary-specific transcription factor PROP1 is present in SOX2-positive cells and disappears at the early stage of the transition from progenitor cell to committed cell during the embryonic development of the rat pituitary. In the present study, we examined the localisation and identification of SOX2-positive and PROP1/SOX2-positive cells in the neonatal and postnatal rat pituitaries by immunohistochemistry. Quantitative analysis of immunoreactive cells demonstrated that SOX2-positive pituitary stem/progenitor cells are not only predominantly localised in the marginal cell layer, but also are scattered in the parenchyma of the adult anterior lobe. In the marginal cell layer, the number of PROP1/SOX2-positive cells significantly decreased after postnatal day 15, indicating that a significant quantitative transition is triggered in the marginal cell layer during the first postnatal growth wave of the anterior pituitary. By contrast, other phenotypes of SOX2-positive stem/progenitor cells that express S100β appeared in the postnatal anterior pituitary. These data suggested that quantitative and qualitative transition occurs by acquisition of a novel mechanism in terminal differentiation in the postnatal development of the anterior pituitary.
Sally A. Camper - One of the best experts on this subject based on the ideXlab platform.
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PROP1-Dependent Retinoic Acid Signaling Regulates Developmental Pituitary Morphogenesis and Hormone Expression
Endocrinology, 2020Co-Authors: Leonard Y.m. Cheung, Sally A. CamperAbstract:Dietary vitamin A is metabolized into bioactive retinoic acid (RA) in vivo and regulates the development of many embryonic tissues. RA signaling is active in the oral ectoderm-derived tissues of the neuroendocrine system, but its role there has not yet been fully explored. We show here that RA signaling is active during pituitary organogenesis and dependent on the pituitary transcription factor PROP1. PROP1-mutant mice show reduced expression of the aldehyde dehydrogenase gene Aldh1a2, which metabolizes the vitamin A-intermediate retinaldehyde into RA. To elucidate the specific function of RA signaling during neuroendocrine development, we studied a conditional deletion of Aldh1a2 and a dominant-negative mouse model of inhibited RA signaling during pituitary organogenesis. These models partially phenocopy PROP1-mutant mice by exhibiting embryonic pituitary dysmorphology and reduced hormone expression, especially thyrotropin. These findings establish the role of RA in embryonic pituitary stem cell progression to differentiated hormone cells and raise the question of gene-by-environment interactions as contributors to pituitary development and disease.
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PROP1 triggers epithelial-mesenchymal transition-like process in pituitary stem cells
eLife, 2016Co-Authors: María Inés Pérez Millán, Michelle L. Brinkmeier, Amanda H. Mortensen, Sally A. CamperAbstract:Mutations in PROP1 are the most common cause of hypopituitarism in humans; therefore, unraveling its mechanism of action is highly relevant from a therapeutic perspective. Our current understanding of the role of PROP1 in the pituitary gland is limited to the repression and activation of the pituitary transcription factor genes Hesx1 and Pou1f1, respectively. To elucidate the comprehensive PROP1-dependent gene regulatory network, we conducted genome-wide analysis of PROP1 DNA binding and effects on gene expression in mutant mice, mouse isolated stem cells and engineered mouse cell lines. We determined that PROP1 is essential for stimulating stem cells to undergo an epithelial to mesenchymal transition-like process necessary for cell migration and differentiation. Genomic profiling reveals that PROP1 binds to genes expressed in epithelial cells like Claudin 23, and to EMT inducer genes like Zeb2, Notch2 and Gli2. Zeb2 activation appears to be a key step in the EMT process. Our findings identify PROP1 as a central transcriptional component of pituitary stem cell differentiation.
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All Hormone-Producing Cell Types of the Pituitary Intermediate and Anterior Lobes Derive From PROP1-Expressing Progenitors
Endocrinology, 2016Co-Authors: Shannon W. Davis, Jessica L. Keisler, María Inés Pérez-millán, Vanessa Schade, Sally A. CamperAbstract:Mutations in PROP1, the most common known cause of combined pituitary hormone deficiency in humans, can result in the progressive loss of all hormones of the pituitary anterior lobe. In mice, PROP1 mutations result in the failure to initiate transcription of Pou1f1 (also known as Pit1) and lack somatotropins, lactotropins, and thyrotropins. The basis for this species difference is unknown. We hypothesized that PROP1 is expressed in a progenitor cell that can develop into all anterior lobe cell types, and not just the somatotropes, thyrotropes, and lactotropes, which are collectively known as the PIT1 lineage. To test this idea, we produced a transgenic PROP1-cre mouse line and conducted lineage-tracing experiments of PROP1-expressing cells. The results reveal that all hormone-secreting cell types of both the anterior and intermediate lobes are descended from PROP1-expressing progenitors. The PROP1-cre mice also provide a valuable genetic reagent with a unique spatial and temporal expression for generating tissue-specific gene rearrangements early in pituitary gland development. We also determined that the minimal essential sequences for reliable PROP1 expression lie within 10 kilobases of the mouse gene and demonstrated that human PROP1 can substitute functionally for mouse PROP1. These studies enhance our understanding of the pathophysiology of disease in patients with PROP1 mutations.
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Aged PROP1 deficient dwarf mice maintain ACTH production.
PloS one, 2011Co-Authors: Igor O. Nasonkin, Robert D Ward, Amanda H. Mortensen, David L. Bavers, Felix Beuschlein, Catherine E. Keegan, Gary D. Hammer, Sally A. CamperAbstract:Humans with PROP1 mutations have multiple pituitary hormone deficiencies (MPHD) that typically advance from growth insufficiency diagnosed in infancy to include more severe growth hormone (GH) deficiency and progressive reduction in other anterior pituitary hormones, eventually including adrenocorticotropic hormone (ACTH) deficiency and hypocortisolism. Congenital deficiencies of GH, prolactin, and thyroid stimulating hormone have been reported in the PROP1null (PROP1-/-) and the Ames dwarf (PROP1df/df) mouse models, but corticotroph and pituitary adrenal axis function have not been thoroughly investigated. Here we report that the C57BL6 background sensitizes mutants to a wasting phenotype that causes approximately one third to die precipitously between weaning and adulthood, while remaining homozygotes live with no signs of illness. The wasting phenotype is associated with severe hypoglycemia. Circulating ACTH and corticosterone levels are elevated in juvenile and aged PROP1 mutants, indicating activation of the pituitary-adrenal axis. Despite this, young adult PROP1 deficient mice are capable of responding to restraint stress with further elevation of ACTH and corticosterone. Low blood glucose, an expected side effect of GH deficiency, is likely responsible for the elevated corticosterone level. These studies suggest that the mouse model differs from the human patients who display progressive hormone loss and hypocortisolism.
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Corepressors TLE1 and TLE3 Interact with HESX1 and PROP1
Molecular endocrinology (Baltimore Md.), 2010Co-Authors: Luciani R. Carvalho, Michelle L. Brinkmeier, Frederic Castinetti, Buffy S. Ellsworth, Sally A. CamperAbstract:Pituitary hormone deficiency causes short stature in one in 4000 children born and can be caused by mutations in transcription factor genes, including HESX1, PROP1, and POU1F1. HESX1 interacts with a member of the groucho-related gene family, TLE1, through an engrailed homology domain and represses PROP1 activity. Mice with PROP1 deficiency exhibit failed differentiation of the POU1F1 lineage, resulting in lack of TSH, GH, and prolactin. In addition, these mutants exhibit profound pituitary dysmorphology and excess Hesx1 and Tle3 expression. The ability of HESX1 to interact with TLE3 has not been explored previously. We tested the ability of TLE3 to enhance HESX1-mediated repression of PROP1 in cell culture. Both TLE3 and TLE1 repress PROP1 in conjunction with HESX1 with similar efficiencies. TLE1 and TLE3 can each repress PROP1 in the absence of HESX1 via a protein-protein interaction. We tested the functional consequences of ectopic TLE3 and HESX1 expression in transgenic mice by driving constitutive expression in pituitary thyrotrophs and gonadotrophs. Terminal differentiation of these cells was suppressed by HESX1 alone and by TLE3 and HESX1 together but not by TLE3 alone. In summary, we present evidence that HESX1 is a strong repressor that can be augmented by the corepressors TLE1 and TLE3. Our in vitro studies suggest that TLE1 and TLE3 might also play roles independent of HESX1 by interacting with other transcription factors like PROP1.
Takako Kato - One of the best experts on this subject based on the ideXlab platform.
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retinoic acid signalling is a candidate regulator of the expression of pituitary specific transcription factor PROP1 in the developing rodent pituitary
Journal of Neuroendocrinology, 2018Co-Authors: Saishu Yoshida, Takako Kato, Hiroto Nishihara, Ken Fujiwara, Takashi Yashiro, Yukio KatoAbstract:Development of the anterior pituitary proceeds via spatiotemporal patterning of transcription factors and signalling molecules. Among them, retinoic acid (RA) functions as an important signalling molecule for vertebrate organogenesis in many tissues. However, little is known regarding the target genes in the developing pituitary. The present study aimed to clarify the relationship between endogenous RA signalling and mRNA expression of the pituitary-specific transcription factor PROP1 in the pituitary primordium of Rathke's pouch. Gene expression analysis and in situ hybridisation demonstrated that retinaldehyde dehydrogenases (Raldhs) and all types of RA receptors (Rars) are expressed at the level of transcription in the rat Rathke's pouch. Ex vivo organ culture using Rathke's pouch and an in vitro reporter assay demonstrated that RA signalling increases the expression level of PROP1 via RARα. Moreover, a reporter assay using serial truncated constructs of the 5'-upstream region of mouse PROP1 revealed a predicted cis-regulatory element of RARα. This is the first report of a relationship between RA signalling and PROP1-expression during early pituitary development.
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Involvement of DNA methylation in regulating rat PROP1 gene expression during pituitary organogenesis.
The Journal of reproduction and development, 2016Co-Authors: Hiroto Nishihara, Takako Kato, Saishu Yoshida, Naoto Nishimura, Hiroki Ueharu, Naoko Kanno, Jun Ohgane, Yukio KatoAbstract: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.
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Search for regulatory factors of the pituitary-specific transcription factor PROP1 gene.
The Journal of reproduction and development, 2015Co-Authors: Naoto Nishimura, Takako Kato, Saishu Yoshida, Hiroki Ueharu, Hiroto Nishihara, Shiori Shibuya, Masashi Higuchi, Naoko Kanno, Kotaro Horiguchi, Yukio KatoAbstract:Pituitary-specific transcription factor PROP1, a factor important for pituitary organogenesis, appears on rat embryonic day 11.5 (E11.5) in SOX2-expressing stem/progenitor cells and always coexists with SOX2 throughout life. PROP1-positive cells at one point occupy all cells in Rathke's pouch, followed by a rapid decrease in their number. Their regulatory factors, except for RBP-J, have not yet been clarified. This study aimed to use the 3 kb upstream region and 1st intron of mouse PROP1 to pinpoint a group of factors selected on the basis of expression in the early pituitary gland for expression of PROP1. Reporter assays for SOX2 and RBP-J showed that the stem/progenitor marker SOX2 has cell type-dependent inhibitory and activating functions through the proximal and distal upstream regions of PROP1, respectively, while RBP-J had small regulatory activity in some cell lines. Reporter assays for another 39 factors using the 3 kb upstream regions in CHO cells ultimately revealed that 8 factors, MSX2, PAX6, PIT1, PITX1, PITX2, RPF1, SOX8 and SOX11, but not RBP-J, regulate PROP1 expression. Furthermore, a synergy effect with SOX2 was observed for an additional 10 factors, FOXJ1, HES1, HEY1, HEY2, KLF6, MSX1, RUNX1, TEAD2, YBX2 and ZFP36Ll, which did not show substantial independent action. Thus, we demonstrated 19 candidates, including SOX2, to be regulatory factors of PROP1 expression.
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Three-dimensional studies of PROP1-expressing cells in the rat pituitary just before birth
Cell and tissue research, 2013Co-Authors: Hideji Yako, Takako Kato, Saishu Yoshida, Hiroki Ueharu, Masashi Higuchi, Naoko Kanno, Mo Chen, Yukio KatoAbstract:Recently, we demonstrated that differentiation was underway as early as embryonic day (E) 13.5 in the lateral region of the rat pituitary primordium. In this study, we analyze the heterogeneous property of cells in the pituitary at E21.5 (just before birth) leading to its biological function with the differentiation and expansion of tissue. The three-dimensional structure of the pituitary at E21.5 was built up from measurements taken from many DAPI-stained sections and cell populations positive to the stem/progenitor marker SOX2, pituitary-specific transcription factor PROP1 and paired-related homeodomain transcription factor PRX. At E21.5, the pituitary, composed of anterior and intermediate lobes, showed a flattened chestnut shape with dimensions of about 500 μm (dorsoventral axis) by 2500 μm (left-right axis) by 850 μm (rostrocaudal axis) and consisted in approximately 113,500, 16,000 and 14,800 cells in the anterior, intermediate and posterior lobes, respectively. Five cell types were observed expressing Sox2, PROP1 and Prx; these were heterogeneously distributed in the mediolateral and dorsoventral axes. In the anterior lobe, the marginal cell layer (MCL) was mostly occupied by stem/progenitor cells positive for SOX2, with the co-expression of PROP1 and/or Prx, whereas more SOX2-single-positive cells than those for PROP1 and PRX were scattered in the parenchyma. PRX-positive cells of mesenchymal origin invaded the parenchyma, together with PECAM- and NESTIN-positive cells, indicating the advance of vasculogenesis. Thus, marked developmental progress occurs regarding the transition of stem/progenitor cells in the MCL and regarding vasculogenesis in the parenchyma during the prenatal pituitary growth wave.
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significant quantitative and qualitative transition in pituitary stem progenitor cells occurs during the postnatal development of the rat anterior pituitary
Journal of Neuroendocrinology, 2011Co-Authors: Saishu Yoshida, Takao Susa, Takako Kato, Hideji Yako, L Y Cai, M Osuna, Kinji Inoue, Yukio KatoAbstract:We reported recently that a pituitary-specific transcription factor PROP1 is present in SOX2-positive cells and disappears at the early stage of the transition from progenitor cell to committed cell during the embryonic development of the rat pituitary. In the present study, we examined the localisation and identification of SOX2-positive and PROP1/SOX2-positive cells in the neonatal and postnatal rat pituitaries by immunohistochemistry. Quantitative analysis of immunoreactive cells demonstrated that SOX2-positive pituitary stem/progenitor cells are not only predominantly localised in the marginal cell layer, but also are scattered in the parenchyma of the adult anterior lobe. In the marginal cell layer, the number of PROP1/SOX2-positive cells significantly decreased after postnatal day 15, indicating that a significant quantitative transition is triggered in the marginal cell layer during the first postnatal growth wave of the anterior pituitary. By contrast, other phenotypes of SOX2-positive stem/progenitor cells that express S100β appeared in the postnatal anterior pituitary. These data suggested that quantitative and qualitative transition occurs by acquisition of a novel mechanism in terminal differentiation in the postnatal development of the anterior pituitary.
Saishu Yoshida - One of the best experts on this subject based on the ideXlab platform.
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retinoic acid signalling is a candidate regulator of the expression of pituitary specific transcription factor PROP1 in the developing rodent pituitary
Journal of Neuroendocrinology, 2018Co-Authors: Saishu Yoshida, Takako Kato, Hiroto Nishihara, Ken Fujiwara, Takashi Yashiro, Yukio KatoAbstract:Development of the anterior pituitary proceeds via spatiotemporal patterning of transcription factors and signalling molecules. Among them, retinoic acid (RA) functions as an important signalling molecule for vertebrate organogenesis in many tissues. However, little is known regarding the target genes in the developing pituitary. The present study aimed to clarify the relationship between endogenous RA signalling and mRNA expression of the pituitary-specific transcription factor PROP1 in the pituitary primordium of Rathke's pouch. Gene expression analysis and in situ hybridisation demonstrated that retinaldehyde dehydrogenases (Raldhs) and all types of RA receptors (Rars) are expressed at the level of transcription in the rat Rathke's pouch. Ex vivo organ culture using Rathke's pouch and an in vitro reporter assay demonstrated that RA signalling increases the expression level of PROP1 via RARα. Moreover, a reporter assay using serial truncated constructs of the 5'-upstream region of mouse PROP1 revealed a predicted cis-regulatory element of RARα. This is the first report of a relationship between RA signalling and PROP1-expression during early pituitary development.
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Involvement of DNA methylation in regulating rat PROP1 gene expression during pituitary organogenesis.
The Journal of reproduction and development, 2016Co-Authors: Hiroto Nishihara, Takako Kato, Saishu Yoshida, Naoto Nishimura, Hiroki Ueharu, Naoko Kanno, Jun Ohgane, Yukio KatoAbstract: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.
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Search for regulatory factors of the pituitary-specific transcription factor PROP1 gene.
The Journal of reproduction and development, 2015Co-Authors: Naoto Nishimura, Takako Kato, Saishu Yoshida, Hiroki Ueharu, Hiroto Nishihara, Shiori Shibuya, Masashi Higuchi, Naoko Kanno, Kotaro Horiguchi, Yukio KatoAbstract:Pituitary-specific transcription factor PROP1, a factor important for pituitary organogenesis, appears on rat embryonic day 11.5 (E11.5) in SOX2-expressing stem/progenitor cells and always coexists with SOX2 throughout life. PROP1-positive cells at one point occupy all cells in Rathke's pouch, followed by a rapid decrease in their number. Their regulatory factors, except for RBP-J, have not yet been clarified. This study aimed to use the 3 kb upstream region and 1st intron of mouse PROP1 to pinpoint a group of factors selected on the basis of expression in the early pituitary gland for expression of PROP1. Reporter assays for SOX2 and RBP-J showed that the stem/progenitor marker SOX2 has cell type-dependent inhibitory and activating functions through the proximal and distal upstream regions of PROP1, respectively, while RBP-J had small regulatory activity in some cell lines. Reporter assays for another 39 factors using the 3 kb upstream regions in CHO cells ultimately revealed that 8 factors, MSX2, PAX6, PIT1, PITX1, PITX2, RPF1, SOX8 and SOX11, but not RBP-J, regulate PROP1 expression. Furthermore, a synergy effect with SOX2 was observed for an additional 10 factors, FOXJ1, HES1, HEY1, HEY2, KLF6, MSX1, RUNX1, TEAD2, YBX2 and ZFP36Ll, which did not show substantial independent action. Thus, we demonstrated 19 candidates, including SOX2, to be regulatory factors of PROP1 expression.
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Three-dimensional studies of PROP1-expressing cells in the rat pituitary just before birth
Cell and tissue research, 2013Co-Authors: Hideji Yako, Takako Kato, Saishu Yoshida, Hiroki Ueharu, Masashi Higuchi, Naoko Kanno, Mo Chen, Yukio KatoAbstract:Recently, we demonstrated that differentiation was underway as early as embryonic day (E) 13.5 in the lateral region of the rat pituitary primordium. In this study, we analyze the heterogeneous property of cells in the pituitary at E21.5 (just before birth) leading to its biological function with the differentiation and expansion of tissue. The three-dimensional structure of the pituitary at E21.5 was built up from measurements taken from many DAPI-stained sections and cell populations positive to the stem/progenitor marker SOX2, pituitary-specific transcription factor PROP1 and paired-related homeodomain transcription factor PRX. At E21.5, the pituitary, composed of anterior and intermediate lobes, showed a flattened chestnut shape with dimensions of about 500 μm (dorsoventral axis) by 2500 μm (left-right axis) by 850 μm (rostrocaudal axis) and consisted in approximately 113,500, 16,000 and 14,800 cells in the anterior, intermediate and posterior lobes, respectively. Five cell types were observed expressing Sox2, PROP1 and Prx; these were heterogeneously distributed in the mediolateral and dorsoventral axes. In the anterior lobe, the marginal cell layer (MCL) was mostly occupied by stem/progenitor cells positive for SOX2, with the co-expression of PROP1 and/or Prx, whereas more SOX2-single-positive cells than those for PROP1 and PRX were scattered in the parenchyma. PRX-positive cells of mesenchymal origin invaded the parenchyma, together with PECAM- and NESTIN-positive cells, indicating the advance of vasculogenesis. Thus, marked developmental progress occurs regarding the transition of stem/progenitor cells in the MCL and regarding vasculogenesis in the parenchyma during the prenatal pituitary growth wave.
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significant quantitative and qualitative transition in pituitary stem progenitor cells occurs during the postnatal development of the rat anterior pituitary
Journal of Neuroendocrinology, 2011Co-Authors: Saishu Yoshida, Takao Susa, Takako Kato, Hideji Yako, L Y Cai, M Osuna, Kinji Inoue, Yukio KatoAbstract:We reported recently that a pituitary-specific transcription factor PROP1 is present in SOX2-positive cells and disappears at the early stage of the transition from progenitor cell to committed cell during the embryonic development of the rat pituitary. In the present study, we examined the localisation and identification of SOX2-positive and PROP1/SOX2-positive cells in the neonatal and postnatal rat pituitaries by immunohistochemistry. Quantitative analysis of immunoreactive cells demonstrated that SOX2-positive pituitary stem/progenitor cells are not only predominantly localised in the marginal cell layer, but also are scattered in the parenchyma of the adult anterior lobe. In the marginal cell layer, the number of PROP1/SOX2-positive cells significantly decreased after postnatal day 15, indicating that a significant quantitative transition is triggered in the marginal cell layer during the first postnatal growth wave of the anterior pituitary. By contrast, other phenotypes of SOX2-positive stem/progenitor cells that express S100β appeared in the postnatal anterior pituitary. These data suggested that quantitative and qualitative transition occurs by acquisition of a novel mechanism in terminal differentiation in the postnatal development of the anterior pituitary.
Takao Susa - One of the best experts on this subject based on the ideXlab platform.
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significant quantitative and qualitative transition in pituitary stem progenitor cells occurs during the postnatal development of the rat anterior pituitary
Journal of Neuroendocrinology, 2011Co-Authors: Saishu Yoshida, Takao Susa, Takako Kato, Hideji Yako, L Y Cai, M Osuna, Kinji Inoue, Yukio KatoAbstract:We reported recently that a pituitary-specific transcription factor PROP1 is present in SOX2-positive cells and disappears at the early stage of the transition from progenitor cell to committed cell during the embryonic development of the rat pituitary. In the present study, we examined the localisation and identification of SOX2-positive and PROP1/SOX2-positive cells in the neonatal and postnatal rat pituitaries by immunohistochemistry. Quantitative analysis of immunoreactive cells demonstrated that SOX2-positive pituitary stem/progenitor cells are not only predominantly localised in the marginal cell layer, but also are scattered in the parenchyma of the adult anterior lobe. In the marginal cell layer, the number of PROP1/SOX2-positive cells significantly decreased after postnatal day 15, indicating that a significant quantitative transition is triggered in the marginal cell layer during the first postnatal growth wave of the anterior pituitary. By contrast, other phenotypes of SOX2-positive stem/progenitor cells that express S100β appeared in the postnatal anterior pituitary. These data suggested that quantitative and qualitative transition occurs by acquisition of a novel mechanism in terminal differentiation in the postnatal development of the anterior pituitary.
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Pituitary homeodomain transcription factors HESX1 and PROP1 form a heterodimer on the inverted TAAT motif.
Molecular and cellular endocrinology, 2009Co-Authors: Yukio Kato, Fuyuko Kimoto, Takao Susa, Michie Nakayama, Akio Ishikawa, Takako KatoAbstract:The development and differentiation of the pituitary gland progress through spatial and temporal expressions of many transcription factors. Transcription factor HESX1, which begins to be expressed in the Rathke's pouch at the early stage of pituitary development, acts as a transcription repressor. Another transcription factor, PROP1, which is a pituitary-specific factor and important for the determination of the differentiation of pituitary hormone-producing cells, appears later than HESX1 and is assumed to block the action of HESX1. Both factors are members of the homeodomain family, and the amino acid residue at the 50th position of the homeodomain is glutamine (Gln-50). We recently observed that both factors share the same target sequence through different binding profiles. Hence, using random oligonucleotides and an electrophoretic mobility-shift assay, we have examined the DNA-binding preference of HESX1 by a determination of its binding sequence. HESX1 binds as a monomer to a TAATT motif but not to a TAAT motif. In the presence of PROP1, HESX1 develops to bind to an inverted TAAT motif by forming a heterodimer. Thus, the formation of a heterodimer between HESX1 and PROP1 provides a condition in which, in the early pituitary primordium, HESX1 alters its repressive role to an active one by forming a heterodimer with newly appearing PROP1 so that PROP1 finally replaces HESX1 to advance to the middle stage of pituitary development.
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PROP1 coexists with SOX2 and induces PIT1-commitment cells.
Biochemical and biophysical research communications, 2009Co-Authors: Saishu Yoshida, Takao Susa, Michie Nakayama, Takako Kato, Li-yi Cai, Yukio KatoAbstract:Abstract Prophet of PIT1 (PROP1) is a pituitary-specific factor and responsive gene for the combined pituitary hormone deficiency in Ames dwarf mice and human patients. Our immunohistochemical studies demonstrated that PROP1 is consistently expressed in SOX2-expressing stem/progenitor cells in the rat pituitary from embryonic (E) to postnatal periods. At E13.5, all the cells in Rathke’s pouch, the primordium of the pituitary, express PROP1. Afterward, PROP1-positive cells localize along the marginal cell layer, a putative stem cell niche in the pituitary, and stratify in the parenchyma of the anterior pituitary. In the embryonic period, PROP1 coexists transiently with PIT1, which is the anterior pituitary-specific factor and is a target of PROP1, but not any hormones. Thus, the present results imply a regulatory role of PROP1 not only in pituitary organogenesis but also in conversion of PIT1-lineage cells.
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Dimeric PROP1 binding to diverse palindromic TAAT sequences promotes its transcriptional activity.
Molecular and cellular endocrinology, 2009Co-Authors: Michie Nakayama, Takao Susa, Takako Kato, Akiko Sano, Kousuke Kitahara, Yukio KatoAbstract:Mutations in the PROP1 gene are responsible for murine Ames dwarfism and human combined pituitary hormone deficiency with hypogonadism. Recently, we reported that PROP1 is a possible transcription factor for gonadotropin subunit genes through plural cis-acting sites composed of AT-rich sequences containing a TAAT motif which differs from its consensus binding sequence known as PRDQ9 (TAATTGAATTA). This study aimed to verify the binding specificity and sequence of PROP1 by applying the method of SELEX (Systematic Evolution of Ligands by EXponential enrichment), EMSA (electrophoretic mobility shift assay) and transient transfection assay. SELEX, after 5, 7 and 9 generations of selection using a random sequence library, showed that nucleotides containing one or two TAAT motifs were accumulated and accounted for 98.5% at the 9th generation. Aligned sequences and EMSA demonstrated that PROP1 binds preferentially to 11 nucleotides composed of an inverted TAAT motif separated by 3 nucleotides with variation in the half site of palindromic TAAT motifs and with preferential requirement of T at the nucleotide number 5 immediately 3' to a TAAT motif. Transient transfection assay demonstrated first that dimeric binding of PROP1 to an inverted TAAT motif and its cognates resulted in transcriptional activation, whereas monomeric binding of PROP1 to a single TAAT motif and an inverted ATTA motif did not mediate activation. Thus, this study demonstrated that dimeric binding of PROP1 is able to recognize diverse palindromic TAAT sequences separated by 3 nucleotides and to exhibit its transcriptional activity.
