The Experts below are selected from a list of 1236 Experts worldwide ranked by ideXlab platform
Richard M Gronostajski - One of the best experts on this subject based on the ideXlab platform.
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NFIA and NFIB function as tumour suppressors in high-grade glioma in mice.
Carcinogenesis, 2020Co-Authors: Kok-siong Chen, Jens Bunt, Zorana Lynton, Richard M Gronostajski, Jonathan W. C. Lim, Thomas Robertson, Linda J. RichardsAbstract:Nuclear factor one (NFI) transcription factors are implicated in both brain development and cancer in mice and humans and play an essential role in glial differentiation. NFI expression is reduced in human astrocytoma samples, particularly those of higher grade, whereas over-expression of NFI protein can induce the differentiation of glioblastoma cells within human tumour xenografts and in glioblastoma cell lines in vitro. These data indicate that NFI proteins may act as tumour suppressors in glioma. To test this hypothesis, we generated complex mouse genetic crosses involving six alleles to target gene deletion of known tumour suppressor genes that induce endogenous high-grade glioma in mice, and overlaid this with loss of function Nfi mutant alleles, NFIA and Nfib, a reporter transgene and an inducible Cre allele. Deletion of Nfi resulted in reduced survival time of the mice, increased tumour load and a more aggressive tumour phenotype than observed in glioma mice with normal expression of NFI. Together, these data indicate that NFI genes represent a credible target for both diagnostic analyses and therapeutic strategies to combat high-grade glioma.
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combined allelic dosage of NFIA and nfib regulates cortical development
Brain and neuroscience advances, 2017Co-Authors: Jens Bunt, Richard M Gronostajski, Linda J. Richards, Jason M. Osinski, Lachlan Harris, Johnathon W C Lim, Diana Vidovic, Oressia Zalucki, Timothy R Oconnor, Michael PiperAbstract:Background:Nuclear factor I family members nuclear factor I A and nuclear factor I B play important roles during cerebral cortical development. Nuclear factor I A and nuclear factor I B regulate si...
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Transcriptional regulation of Nfix by NFIB drives astrocytic maturation within the developing spinal cord.
Developmental biology, 2017Co-Authors: Elise Matuzelski, Jens Bunt, Richard M Gronostajski, Linda J. Richards, Jonathan W. C. Lim, Lachlan Harris, Danyon Harkins, Michael PiperAbstract:During mouse spinal cord development, ventricular zone progenitor cells transition from producing neurons to producing glia at approximately embryonic day 11.5, a process known as the gliogenic switch. The transcription factors Nuclear Factor I (NFI) A and B initiate this developmental transition, but the contribution of a third NFI member, NFIX, remains unknown. Here, we reveal that ventricular zone progenitor cells within the spinal cord express NFIX after the onset of NFIA and NFIB expression, and after the gliogenic switch has occurred. Mice lacking NFIX exhibit normal neurogenesis within the spinal cord, and, while early astrocytic differentiation proceeds normally, aspects of terminal astrocytic differentiation are impaired. Finally, we report that, in the absence of NFIA or Nfib, there is a marked reduction in the spinal cord expression of NFIX, and that NFIB can transcriptionally activate Nfix expression in vitro. These data demonstrate that NFIX is part of the downstream transcriptional program through which NFIA and NFIB coordinate gliogenesis within the spinal cord. This hierarchical organisation of NFI protein expression and function during spinal cord gliogenesis reveals a previously unrecognised auto-regulatory mechanism within this gene family.
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cell type specific expression of nfix in the developing and adult cerebellum
Brain Structure & Function, 2017Co-Authors: James Fraser, Richard M Gronostajski, Alexandra Essebier, Mikael Boden, Brandon J Wainwright, Tracey J Harvey, Michael PiperAbstract:Transcription factors from the nuclear factor one (NFI) family have been shown to play a central role in regulating neural progenitor cell differentiation within the embryonic and post-natal brain. NFIA and NFIB, for instance, promote the differentiation and functional maturation of granule neurons within the cerebellum. Mice lacking Nfix exhibit delays in the development of neuronal and glial lineages within the cerebellum, but the cell-type-specific expression of this transcription factor remains undefined. Here, we examined the expression of NFIX, together with various cell-type-specific markers, within the developing and adult cerebellum using both chromogenic immunohistochemistry and co-immunofluorescence labelling and confocal microscopy. In embryos, NFIX was expressed by progenitor cells within the rhombic lip and ventricular zone. After birth, progenitor cells within the external granule layer, as well as migrating and mature granule neurons, expressed NFIX. Within the adult cerebellum, NFIX displayed a broad expression profile, and was evident within granule cells, Bergmann glia, and interneurons, but not within Purkinje neurons. Furthermore, transcriptomic profiling of cerebellar granule neuron progenitor cells showed that multiple splice variants of Nfix are expressed within this germinal zone of the post-natal brain. Collectively, these data suggest that NFIX plays a role in regulating progenitor cell biology within the embryonic and post-natal cerebellum, as well as an ongoing role within multiple neuronal and glial populations within the adult cerebellum.
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Heterozygosity for nuclear factor one x affects hippocampal-dependent behaviour in mice.
PloS one, 2013Co-Authors: Lachlan Harris, Richard M Gronostajski, Linda J. Richards, Kathleen Cato, Yee Hsieh Evelyn Heng, Chantelle Dixon, Nyoman D. Kurniawan, Jeremy F.p. Ullmann, Andrew L. Janke, Thomas H. J. BurneAbstract:Identification of the genes that regulate the development and subsequent functioning of the hippocampus is pivotal to understanding the role of this cortical structure in learning and memory. One group of genes that has been shown to be critical for the early development of the hippocampus is the Nuclear factor one (Nfi) family, which encodes four site-specific transcription factors, NFIA, NFIB, NFIC and NFIX. In mice lacking NFIA, Nfib or Nfix, aspects of early hippocampal development, including neurogenesis within the dentate gyrus, are delayed. However, due to the perinatal lethality of these mice, it is not clear whether this hippocampal phenotype persists to adulthood and affects hippocampal-dependent behaviour. To address this we examined the hippocampal phenotype of mice heterozygous for Nfix (Nfix+/−), which survive to adulthood. We found that Nfix+/− mice had reduced expression of NFIX throughout the brain, including the hippocampus, and that early hippocampal development in these mice was disrupted, producing a phenotype intermediate to that of wild-type mice and Nfix−/− mice. The abnormal hippocampal morphology of Nfix+/− mice persisted to adulthood, and these mice displayed a specific performance deficit in the Morris water maze learning and memory task. These findings demonstrate that the level of Nfix expression during development and within the adult is essential for the function of the hippocampus during learning and memory.
Linda J. Richards - One of the best experts on this subject based on the ideXlab platform.
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NFIA and NFIB function as tumour suppressors in high-grade glioma in mice.
Carcinogenesis, 2020Co-Authors: Kok-siong Chen, Jens Bunt, Zorana Lynton, Richard M Gronostajski, Jonathan W. C. Lim, Thomas Robertson, Linda J. RichardsAbstract:Nuclear factor one (NFI) transcription factors are implicated in both brain development and cancer in mice and humans and play an essential role in glial differentiation. NFI expression is reduced in human astrocytoma samples, particularly those of higher grade, whereas over-expression of NFI protein can induce the differentiation of glioblastoma cells within human tumour xenografts and in glioblastoma cell lines in vitro. These data indicate that NFI proteins may act as tumour suppressors in glioma. To test this hypothesis, we generated complex mouse genetic crosses involving six alleles to target gene deletion of known tumour suppressor genes that induce endogenous high-grade glioma in mice, and overlaid this with loss of function Nfi mutant alleles, NFIA and Nfib, a reporter transgene and an inducible Cre allele. Deletion of Nfi resulted in reduced survival time of the mice, increased tumour load and a more aggressive tumour phenotype than observed in glioma mice with normal expression of NFI. Together, these data indicate that NFI genes represent a credible target for both diagnostic analyses and therapeutic strategies to combat high-grade glioma.
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combined allelic dosage of NFIA and nfib regulates cortical development
Brain and neuroscience advances, 2017Co-Authors: Jens Bunt, Richard M Gronostajski, Linda J. Richards, Jason M. Osinski, Lachlan Harris, Johnathon W C Lim, Diana Vidovic, Oressia Zalucki, Timothy R Oconnor, Michael PiperAbstract:Background:Nuclear factor I family members nuclear factor I A and nuclear factor I B play important roles during cerebral cortical development. Nuclear factor I A and nuclear factor I B regulate si...
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Transcriptional regulation of Nfix by NFIB drives astrocytic maturation within the developing spinal cord.
Developmental biology, 2017Co-Authors: Elise Matuzelski, Jens Bunt, Richard M Gronostajski, Linda J. Richards, Jonathan W. C. Lim, Lachlan Harris, Danyon Harkins, Michael PiperAbstract:During mouse spinal cord development, ventricular zone progenitor cells transition from producing neurons to producing glia at approximately embryonic day 11.5, a process known as the gliogenic switch. The transcription factors Nuclear Factor I (NFI) A and B initiate this developmental transition, but the contribution of a third NFI member, NFIX, remains unknown. Here, we reveal that ventricular zone progenitor cells within the spinal cord express NFIX after the onset of NFIA and NFIB expression, and after the gliogenic switch has occurred. Mice lacking NFIX exhibit normal neurogenesis within the spinal cord, and, while early astrocytic differentiation proceeds normally, aspects of terminal astrocytic differentiation are impaired. Finally, we report that, in the absence of NFIA or Nfib, there is a marked reduction in the spinal cord expression of NFIX, and that NFIB can transcriptionally activate Nfix expression in vitro. These data demonstrate that NFIX is part of the downstream transcriptional program through which NFIA and NFIB coordinate gliogenesis within the spinal cord. This hierarchical organisation of NFI protein expression and function during spinal cord gliogenesis reveals a previously unrecognised auto-regulatory mechanism within this gene family.
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PAX6 does not regulate NFIA and Nfib expression during neocortical development.
Scientific reports, 2015Co-Authors: Jens Bunt, Sharon Mason, Jonathan W. C. Lim, Lu Zhao, Linda J. RichardsAbstract:The Nuclear factor I (NFI) family of transcription factors regulates proliferation and differentiation throughout the developing central nervous system. In the developing telencephalon of humans and mice, reduced Nfi expression is associated with agenesis of the corpus callosum and other neurodevelopmental defects. Currently, little is known about how Nfi expression is regulated during early telencephalic development. PAX6, a transcription factor important for telencephalic development, has been proposed as an upstream regulator of Nfi expression in the neocortex. Here we demonstrate that, in the developing neocortex of mice, NFIA and NFIB are endogenously expressed in gradients with high caudo-medial to low rostro-lateral expression and are most highly expressed in the cortical plate. We found that this expression pattern deviates from that of PAX6, suggesting that PAX6 does not drive Nfi expression. This is supported by in vitro reporter assays showing that PAX6 over-expression does not regulate Nfi promoter activity. Similarly, we also found that in the Pax6 Small Eye mutant, no changes in Nfi mRNA or protein expression are observed in the neocortical ventricular zone where PAX6 and the NFIs are expressed. Together these data demonstrate that in mice, PAX6 is not a transcriptional activator of Nfi expression during neocortical development.
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Heterozygosity for nuclear factor one x affects hippocampal-dependent behaviour in mice.
PloS one, 2013Co-Authors: Lachlan Harris, Richard M Gronostajski, Linda J. Richards, Kathleen Cato, Yee Hsieh Evelyn Heng, Chantelle Dixon, Nyoman D. Kurniawan, Jeremy F.p. Ullmann, Andrew L. Janke, Thomas H. J. BurneAbstract:Identification of the genes that regulate the development and subsequent functioning of the hippocampus is pivotal to understanding the role of this cortical structure in learning and memory. One group of genes that has been shown to be critical for the early development of the hippocampus is the Nuclear factor one (Nfi) family, which encodes four site-specific transcription factors, NFIA, NFIB, NFIC and NFIX. In mice lacking NFIA, Nfib or Nfix, aspects of early hippocampal development, including neurogenesis within the dentate gyrus, are delayed. However, due to the perinatal lethality of these mice, it is not clear whether this hippocampal phenotype persists to adulthood and affects hippocampal-dependent behaviour. To address this we examined the hippocampal phenotype of mice heterozygous for Nfix (Nfix+/−), which survive to adulthood. We found that Nfix+/− mice had reduced expression of NFIX throughout the brain, including the hippocampus, and that early hippocampal development in these mice was disrupted, producing a phenotype intermediate to that of wild-type mice and Nfix−/− mice. The abnormal hippocampal morphology of Nfix+/− mice persisted to adulthood, and these mice displayed a specific performance deficit in the Morris water maze learning and memory task. These findings demonstrate that the level of Nfix expression during development and within the adult is essential for the function of the hippocampus during learning and memory.
Michael Piper - One of the best experts on this subject based on the ideXlab platform.
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combined allelic dosage of NFIA and nfib regulates cortical development
Brain and neuroscience advances, 2017Co-Authors: Jens Bunt, Richard M Gronostajski, Linda J. Richards, Jason M. Osinski, Lachlan Harris, Johnathon W C Lim, Diana Vidovic, Oressia Zalucki, Timothy R Oconnor, Michael PiperAbstract:Background:Nuclear factor I family members nuclear factor I A and nuclear factor I B play important roles during cerebral cortical development. Nuclear factor I A and nuclear factor I B regulate si...
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Transcriptional regulation of Nfix by NFIB drives astrocytic maturation within the developing spinal cord.
Developmental biology, 2017Co-Authors: Elise Matuzelski, Jens Bunt, Richard M Gronostajski, Linda J. Richards, Jonathan W. C. Lim, Lachlan Harris, Danyon Harkins, Michael PiperAbstract:During mouse spinal cord development, ventricular zone progenitor cells transition from producing neurons to producing glia at approximately embryonic day 11.5, a process known as the gliogenic switch. The transcription factors Nuclear Factor I (NFI) A and B initiate this developmental transition, but the contribution of a third NFI member, NFIX, remains unknown. Here, we reveal that ventricular zone progenitor cells within the spinal cord express NFIX after the onset of NFIA and NFIB expression, and after the gliogenic switch has occurred. Mice lacking NFIX exhibit normal neurogenesis within the spinal cord, and, while early astrocytic differentiation proceeds normally, aspects of terminal astrocytic differentiation are impaired. Finally, we report that, in the absence of NFIA or Nfib, there is a marked reduction in the spinal cord expression of NFIX, and that NFIB can transcriptionally activate Nfix expression in vitro. These data demonstrate that NFIX is part of the downstream transcriptional program through which NFIA and NFIB coordinate gliogenesis within the spinal cord. This hierarchical organisation of NFI protein expression and function during spinal cord gliogenesis reveals a previously unrecognised auto-regulatory mechanism within this gene family.
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cell type specific expression of nfix in the developing and adult cerebellum
Brain Structure & Function, 2017Co-Authors: James Fraser, Richard M Gronostajski, Alexandra Essebier, Mikael Boden, Brandon J Wainwright, Tracey J Harvey, Michael PiperAbstract:Transcription factors from the nuclear factor one (NFI) family have been shown to play a central role in regulating neural progenitor cell differentiation within the embryonic and post-natal brain. NFIA and NFIB, for instance, promote the differentiation and functional maturation of granule neurons within the cerebellum. Mice lacking Nfix exhibit delays in the development of neuronal and glial lineages within the cerebellum, but the cell-type-specific expression of this transcription factor remains undefined. Here, we examined the expression of NFIX, together with various cell-type-specific markers, within the developing and adult cerebellum using both chromogenic immunohistochemistry and co-immunofluorescence labelling and confocal microscopy. In embryos, NFIX was expressed by progenitor cells within the rhombic lip and ventricular zone. After birth, progenitor cells within the external granule layer, as well as migrating and mature granule neurons, expressed NFIX. Within the adult cerebellum, NFIX displayed a broad expression profile, and was evident within granule cells, Bergmann glia, and interneurons, but not within Purkinje neurons. Furthermore, transcriptomic profiling of cerebellar granule neuron progenitor cells showed that multiple splice variants of Nfix are expressed within this germinal zone of the post-natal brain. Collectively, these data suggest that NFIX plays a role in regulating progenitor cell biology within the embryonic and post-natal cerebellum, as well as an ongoing role within multiple neuronal and glial populations within the adult cerebellum.
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Expression of nuclear factor one A and -B in the olfactory bulb.
The Journal of comparative neurology, 2012Co-Authors: Celine Plachez, Richard M Gronostajski, Linda J. Richards, Kathleen Cato, Robert C. Mcleay, Yee Hsieh Evelyn Heng, Timothy L. Bailey, Adam C. Puche, Michael PiperAbstract:The nuclear factor one (NFI) family of transcription factors consists of four members in vertebrates, NFIA, NFIB, NFIC, and NFIX, which share a highly conserved N-terminal DNA-binding domain. NFI genes are widely expressed in the developing mouse brain, and mouse mutants lacking NFIA, NFIB, or NFIX exhibit developmental deficits in several areas, including the cortex, hippocampus, pons, and cerebellum. Here we analyzed the expression of NFIA and NFIB in the developing and adult olfactory bulb (OB), rostral migratory stream (RMS), and subventricular zone (SVZ). We found that NFIA and NFIB are expressed within these regions during embryonic and postnatal development and in the adult. Immunohistochemical analysis using cell-type-specific markers revealed that migrating neuroblasts in the adult brain express NFI transcription factors, as do astrocytes within the RMS and progenitor cells within the SVZ. Moreover, astrocytes within the OB express NFIA, whereas mitral cells within the OB express NFIB. Taken together these data show that NFIA and NFIB are expressed in both the developing and the adult OB and in the RMS and SVZ, indicative of a regulatory role for these transcription factors in the development of this facet of the olfactory system.
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Nuclear Factor One Transcription Factors in CNS Development
Molecular Neurobiology, 2009Co-Authors: Sharon Mason, Richard M Gronostajski, Michael Piper, Linda J. RichardsAbstract:Transcription factors are key regulators of central nervous system (CNS) development and brain function. Research in this area has now uncovered a new key player–the nuclear factor one (NFI) gene family. It has been almost a decade since the phenotype of the null mouse mutant for the nuclear factor one A transcription factor was reported. NFIA null mice display a striking brain phenotype including agenesis of the corpus callosum and malformation of midline glial populations needed to guide axons of the corpus callosum across the midline of the developing brain. Besides NFIA, there are three other NFI family members in vertebrates: NFIB, NFIC, and NFIX. Since generation of the NFIA knockout (KO) mice, KO mice for all other family members have been generated, and defects in one or more organ systems have been identified for all four NFI family members (collectively referred to as NFI here). Like the NFIA KO mice, the Nfib and Nfix KO mice also display a brain phenotype, with the Nfib KO forebrain phenotype being remarkably similar to that of NFIA . Over the past few years, studies have highlighted NFI as a key payer in a variety of CNS processes including axonal outgrowth and guidance and glial and neuronal cell differentiation. Here, we discuss the importance and role of NFI in these processes in the context of several CNS systems including the neocortex, hippocampus, cerebellum, and spinal cord at both cellular and molecular levels.
Junyao Yang - One of the best experts on this subject based on the ideXlab platform.
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rp5 833a20 1 mir 382 5p NFIA dependent signal transduction pathway contributes to the regulation of cholesterol homeostasis and inflammatory reaction
Arteriosclerosis Thrombosis and Vascular Biology, 2015Co-Authors: Yanwei Hu, Jiayi Zhao, Shufen Li, Jinlan Huang, Shaoguo Wu, Zhiping Chen, Yarong Hu, Junyao Yang, Yanchao Wang, Lei ZhengAbstract:Objective— Cardiovascular disease caused by atherosclerosis is the number one cause of death in Western countries and threatens to become the major cause of morbidity and mortality worldwide. Long noncoding RNAs are emerging as new players in gene regulation, but how long noncoding RNAs operate in the development of atherosclerosis remains unclear. Approach and Results— Using microarray analysis, we found that long noncoding RNA RP5-833A20.1 expression was upregulated, whereas nuclear factor IA (NFIA) expression was downregulated in human acute monocytic leukemia macrophage–derived foam cells. Moreover, we showed that long noncoding RNA RP5-833A20.1 may decreases NFIA expression by inducing hsa-miR-382-5p expression in vitro. We found that the RP5-833A20.1/hsa-miR-382-5p/NFIA pathway is essential to the regulation of cholesterol homeostasis and inflammatory responses in human acute monocytic leukemia macrophages. Lentivirus-mediated NFIA overexpression increased high-density lipoprotein cholesterol circulation, reduced low-density lipoprotein cholesterol, and very-low-density lipoprotein cholesterol circulation, decreased circulation of inflammatory cytokines, including interleukin-1β, interleukin-6, tumor necrosis factor-α, and C-reactive protein, enhanced reverse cholesterol transport, and promoted regression of atherosclerosis in apolipoprotein E–deficient mice. Conclusions— Our findings indicated that the RP5-833A20.1/miR-382-5p/NFIA pathway was essential to the regulation of cholesterol homeostasis and inflammatory reactions and suggested that NFIA may represent a therapeutic target to ameliorate cardiovascular disease. # Significance {#article-title-67}
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RP5-833A20.1/miR-382-5p/NFIA–Dependent Signal Transduction Pathway Contributes to the Regulation of Cholesterol Homeostasis and Inflammatory Reaction
Arteriosclerosis thrombosis and vascular biology, 2014Co-Authors: Jiayi Zhao, Yu-rong Qiu, Jinlan Huang, Zhiping Chen, Junyao YangAbstract:Objective— Cardiovascular disease caused by atherosclerosis is the number one cause of death in Western countries and threatens to become the major cause of morbidity and mortality worldwide. Long noncoding RNAs are emerging as new players in gene regulation, but how long noncoding RNAs operate in the development of atherosclerosis remains unclear. Approach and Results— Using microarray analysis, we found that long noncoding RNA RP5-833A20.1 expression was upregulated, whereas nuclear factor IA (NFIA) expression was downregulated in human acute monocytic leukemia macrophage–derived foam cells. Moreover, we showed that long noncoding RNA RP5-833A20.1 may decreases NFIA expression by inducing hsa-miR-382-5p expression in vitro. We found that the RP5-833A20.1/hsa-miR-382-5p/NFIA pathway is essential to the regulation of cholesterol homeostasis and inflammatory responses in human acute monocytic leukemia macrophages. Lentivirus-mediated NFIA overexpression increased high-density lipoprotein cholesterol circulation, reduced low-density lipoprotein cholesterol, and very-low-density lipoprotein cholesterol circulation, decreased circulation of inflammatory cytokines, including interleukin-1β, interleukin-6, tumor necrosis factor-α, and C-reactive protein, enhanced reverse cholesterol transport, and promoted regression of atherosclerosis in apolipoprotein E–deficient mice. Conclusions— Our findings indicated that the RP5-833A20.1/miR-382-5p/NFIA pathway was essential to the regulation of cholesterol homeostasis and inflammatory reactions and suggested that NFIA may represent a therapeutic target to ameliorate cardiovascular disease. # Significance {#article-title-67}
Benjamin Deneen - One of the best experts on this subject based on the ideXlab platform.
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Region-Specific Transcriptional Control of Astrocyte Function Oversees Local Circuit Activities
Neuron, 2020Co-Authors: Anna Yu-szu Huang, Navish A. Bosquez Huerta, Debosmita Sardar, Junsung Woo, Brittney Lozzi, Chia-ching John Lin, Daniela F. Felice, Antrix Jain, Adriana Paulucci-holthauzen, Benjamin DeneenAbstract:Summary Astrocytes play essential roles in brain function by supporting synaptic connectivity and associated circuits. How these roles are regulated by transcription factors is unknown. Moreover, there is emerging evidence that astrocytes exhibit regional heterogeneity, and the mechanisms controlling this diversity remain nascent. Here, we show that conditional deletion of the transcription factor nuclear factor I-A (NFIA) in astrocytes in the adult brain results in region-specific alterations in morphology and physiology that are mediated by selective DNA binding. Disruptions in astrocyte function following loss of NFIA are most pronounced in the hippocampus, manifested by impaired interactions with neurons, coupled with diminution of learning and memory behaviors. These changes in hippocampal astrocytes did not affect basal neuronal properties but specifically inhibited synaptic plasticity, which is regulated by NFIA in astrocytes through calcium-dependent mechanisms. Together, our studies reveal region-specific transcriptional dependencies for astrocytes and identify astrocytic NFIA as a key transcriptional regulator of hippocampal circuits.
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Nuclear factor IA is expressed in astrocytomas and is associated with improved survival
2016Co-Authors: Hae-ri Song, Benjamin Deneen, Ignacio Gonzalez-gomez, Greg S. Suh, Deborah L. Commins, Richard Sposto, Floyd H. Gilles, Anat Erdreich-epsteinAbstract:Nuclear factor IA (NFIA) is a transcription factor that specifies glial cell identity and promotes astrocyte differ-entiation during embryonic development. Its expression and function in gliomas are not known. Here, we exam-ined NFIA protein expression in gliomas and its associ-ation with clinical outcome in pediatric malignant astrocytomas. We analyzed expression of NFIA by immunohistochemistry in 88 existing glioma specimens from Childrens Hospital Los Angeles and the University of Southern California. Association between NFIA expression and progression-free survival (PFS) was examined in high-grade astrocytomas for which clinical data were available (n 5 23, all children). NFIA was highly expressed in astrocytomas of all grades, but only in a minority of cells in oligodendroglia
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Mutual antagonism between Sox10 and NFIA regulates diversification of glial lineages and glioma subtypes
Nature neuroscience, 2014Co-Authors: Stacey M. Glasgow, Teng-wei Huang, Carrie A. Mohila, Wenyi Zhu, C. Claus Stolt, Fuyi Chen, Joseph J. Loturco, Jeffrey L. Neul, Michael Wegner, Benjamin DeneenAbstract:Lineage progression and diversification is regulated by the coordinated action of unique sets of transcription factors. Oligodendrocytes (OL) and astrocytes (AS) comprise the glial sub-lineages in the CNS, and the manner in which their associated regulatory factors orchestrate lineage diversification during development and disease remains an open question. Sox10 and NFIA are key transcriptional regulators of gliogenesis associated with OL and AS. We found that NFIA inhibited Sox10 induction of OL differentiation through direct association and antagonism of its function. Conversely, we found that Sox10 antagonized NFIA function and suppressed AS differentiation in mouse and chick systems. Using this developmental paradigm as a model for glioma, we found that this relationship similarly regulated the generation of glioma subtypes. Our results describe the antagonistic relationship between Sox10 and NFIA that regulates the balance of OL and AS fate during development and demonstrate for the first time, to the best of our knowledge, that the transcriptional processes governing glial sub-lineage diversification oversee the generation of glioma subtypes.
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A novel tumor-promoting role for nuclear factor IA in glioblastomas is mediated through negative regulation of p53, p21, and PAI1
Neuro-oncology, 2013Co-Authors: Junsung Lee, Benjamin Deneen, Jiping Xiao, Parita Patel, Jake Schade, Jinhua Wang, Anat Erdreich-epstein, Hae-ri SongAbstract:Background Nuclear factor IA (NFIA), a transcription factor and essential regulator in embryonic glial development, is highly expressed in human glioblastoma (GBM) compared with normal brain, but its contribution to GBM and cancer pathogenesis is unknown. Here we demonstrate a novel role for NFIA in promoting growth and migration of GBM and establish the molecular mechanisms mediating these functions. Methods To determine the role of NFIA in glioma, we examined the effects of NFIA in growth, proliferation, apoptosis, and migration. We used gain-of-function (overexpression) and loss-of-function (shRNA knockdown) of NFIA in primary patient-derived GBM cells and established glioma cell lines in culture and in intracranial xenografts in mouse brains. Results Knockdown of native NFIA blocked tumor growth and induced cell death and apoptosis. Complementing this, NFIA overexpression accelerated growth, proliferation, and migration of GBM in cell culture and in mouse brains. These NFIA tumor-promoting effects were mediated via transcriptional repression of p53, p21, and plasminogen activator inhibitor 1 (PAI1) through specific NFIA-recognition sequences in their promoters. Importantly, the effects of NFIA on proliferation and apoptosis were independent of TP53 mutation status, a finding especially relevant for GBM, in which TP53 is frequently mutated. Conclusion NFIA is a modulator of GBM growth and migration, and functions by distinct regulation of critical oncogenic pathways that govern the malignant behavior of GBM.
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Evidence that nuclear factor IA inhibits repair after white matter injury.
Annals of neurology, 2012Co-Authors: Stephen P.j. Fancy, Stacey M. Glasgow, Meggie Finley, David H. Rowitch, Benjamin DeneenAbstract:Objective: Chronic demyelination can result in axonopathy and is associated with human neurological conditions such as multiple sclerosis (MS) in adults and cerebral palsy in infants. In these disorders, myelin regeneration is inhibited by impaired differentiation of oligodendrocyte progenitors into myelin-producing oligodendrocytes. However, regulatory factors relevant in human myelin disorders and in myelin regeneration remain poorly understood. Here we have investigated the role of the transcription factor nuclear factor IA (NFIA) in oligodendrocyte progenitor differentiation during developmental and regenerative myelination. Methods: NFIA expression patterns in human neonatal hypoxic–ischemic encephalopathy (HIE) and MS as well as developmental expression in mice were evaluated. Functional studies during remyelination were performed using a lysolecithin model, coupled with lentiviral misexpression of NFIA. The role of NFIA during oligodendrocyte lineage development was characterized using chick and mouse models and in vitro culture of oligodendrocyte progenitors. Biochemical mechanism of NFIA function was evaluated using chromatin immunoprecipitation and reporter assays. Results: NFIA is expressed in oligodendrocyte progenitors, but not differentiated oligodendrocytes during mouse embryonic development. Examination of NFIA expression in white matter lesions of human newborns with neonatal HIE, as well active MS lesions in adults, revealed that it is similarly expressed in oligodendrocyte progenitors and not oligodendrocytes. Functional studies indicate that NFIA is sufficient to suppress oligodendrocyte progenitor differentiation during adult remyelination and embryonic development through direct repression of myelin gene expression. Interpretation: These studies suggest that NFIA participates in the control of oligodendrocyte progenitor differentiation and may contribute to the inhibition of remyelination in human myelin disorders. ANN NEUROL 2012;