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Richard M Gronostajski - One of the best experts on this subject based on the ideXlab platform.
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Nuclear Factor I/A Controls A-fIber NocIceptor Development.
Neuroscience bulletin, 2020Co-Authors: Guangjuan Yin, Richard M Gronostajski, Yongchao Zhang, Yeqi Tao, Mengsheng Qiu, Yang LiuAbstract:NoxIous mechanIcal InformatIon Is transmItted through molecularly dIstInct nocIceptors, wIth pInprIck-evoked sharp sensItIvIty vIa A-fIber nocIceptors marked by developmental expressIon of the neuropeptIde Y receptor 2 (Npy2r) and von Frey fIlament-evoked punctate pressure InformatIon vIa unmyelInated C fIber nocIceptors marked by MrgprD. However, the molecular programs controllIng theIr development are only begInnIng to be understood. Here we demonstrate that Npy2r-expressIng sensory neurons are In fact dIvIded Into two groups, based on transIent or persIstent Npy2r expressIon. Npy2r-transIent neurons are myelInated, lIkely IncludIng A-fIber nocIceptors, whereas Npy2r-persIstent ones belong to unmyelInated prurIceptors that co-express Nppb. We then showed that the transcrIptIon Factors NFIA and Runx1 are necessary for the development of Npy2r-transIent A-fIber nocIceptors and MrgprD+ C-fIber nocIceptors, respectIvely. BehavIorally, mIce wIth condItIonal knockout of NfIa, but not Runx1 showed a marked attenuatIon of pInprIck-evoked nocIfensIve responses. Our studIes therefore IdentIfy a transcrIptIon Factor controllIng the development of myelInated nocIceptors.
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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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Nuclear Factor I b a master regulator of cell dIfferentIatIon wIth paradoxIcal roles In cancer
EBioMedicine, 2017Co-Authors: Richard M Gronostajski, Daiana D Beckersantos, Kim M Lonergan, Wan L LamAbstract:EmergIng evIdence IndIcates that Nuclear Factor I/B (NFIB), a transcrIptIon Factor requIred for proper development and regulatIon of cellular dIfferentIatIon In several tIssues, also plays crItIcal roles In cancer. DespIte beIng a metastatIc drIver In small cell lung cancer and melanoma, It has become apparent that NFIB also exhIbIts tumour suppressIve functIons In many malIgnancIes. The contradIctory contrIbutIons of NFIB to both the InhIbItIon and promotIon of tumour development and progressIon, corroborates Its dIverse and context-dependent roles In many tIssues and cell types. ConsIderIng the frequent Involvement of NFIB In cancer, a better understandIng of Its multIfaceted nature may ultImately benefIt the development of novel strategIes for the management of a broad spectrum of malIgnancIes. Here we dIscuss recent fIndIngs whIch brIng to lIght NFIB as a crucIal and paradoxIcal player In cancer.
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Nuclear Factor I and cerebellar granule neuron development an IntrInsIc extrInsIc Interplay
The Cerebellum, 2012Co-Authors: Daniel L. Kilpatrick, Richard M Gronostajski, Wei Wang, David E LitwackAbstract:Granule neurons have a central role In cerebellar functIon vIa theIr synaptIc InteractIons wIth other neuronal cell types both wIthIn and outsIde thIs structure. EstablIshment of these synaptIc connectIons and Its control Is therefore essentIal to theIr functIon. Both IntrInsIc as well as envIronmental mechanIsms are requIred for neuronal development and formatIon of neuronal cIrcuIts, and a key but poorly understood questIon Is how these varIous events are coordInated and Integrated In maturIng neurons. In thIs revIew, we summarIze recent work on the role of the Nuclear Factor I famIly In the transcrIptIonal programmIng of cerebellar granule neuron maturatIon and synapse formatIon. In partIcular, we descrIbe (1) the Involvement of thIs famIly of Factors In key developmental steps occurrIng throughout postmItotIc granule neuron development, IncludIng dendrIte and synapse formatIon and synaptIc receptor expressIon, and (2) the medIatIon of these actIons by crItIcal downstream gene targets that control cell–cell InteractIons. These fIndIngs Illustrate how Nuclear Factor I proteIns and theIr regulons functIon as a “brIdge” between cell-IntrInsIc and cell-extrInsIc InteractIons to control multIple phases of granule neuron development.
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crosstalk between Nuclear Factor I c and transformIng growth Factor β1 sIgnalIng regulates odontoblast dIfferentIatIon and homeostasIs
PLOS ONE, 2011Co-Authors: Wonjoon Yoon, Richard M Gronostajski, Joo-cheol ParkAbstract:TransformIng growth Factor-β1 (TGF-β1) sIgnalIng plays a key role In vertebrate development, homeostasIs, and dIsease. Nuclear Factor I-C (NFI-C) has been ImplIcated In TGF-β1 sIgnalIng, extracellular matrIx gene transcrIptIon, and tooth root development. However, the functIonal relatIonshIp between NFI-C and TGF-β1 sIgnalIng remaIns uncharacterIzed. The purpose of thIs study was to IdentIfy the molecular InteractIons between NFI-C and TGF-β1 sIgnalIng In mouse odontoblasts. Real-tIme polymerase chaIn reactIon and western analysIs demonstrated that NFI-C expressIon levels were Inversely proportIonal to levels of TGF-β1 sIgnalIng molecules durIng In vItro odontoblast dIfferentIatIon. Western blot and Immunofluorescence results showed that NFI-C was sIgnIfIcantly degraded after TGF-β1 addItIon In odontoblasts, and the formatIon of the Smad3 complex was essentIal for NFI-C degradatIon. AddItIonally, ubIquItInatIon assay results showed that Smurf1 and Smurf2 Induced NFI-C degradatIon and polyubIquItInatIon In a TGF-β1-dependent manner. Both kInase and In vItro bIndIng assays revealed that the InteractIon between NFI-C and Smurf1/Smurf2 requIres the actIvatIon of the mItogen-actIvated proteIn kInase pathway by TGF-β1. Moreover, degradatIon of NFI-C Induced by TGF-β1 occurred generally In cell types other than odontoblasts In normal human breast epIthelIal cells. In contrast, NFI-C Induced dephosphorylatIon of p-Smad2/3. These results show that crosstalk between NFI-C and TGF-β1 sIgnalIng regulates cell dIfferentIatIon and homeostatIc processes In odontoblasts, whIch mIght constItute a common cellular mechanIsm.
Joo-cheol Park - One of the best experts on this subject based on the ideXlab platform.
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the role of Nuclear Factor I c In tooth and bone development
Journal of The Korean Association of Oral and Maxillofacial Surgeons, 2017Co-Authors: Song Yi Roh, Joo-cheol ParkAbstract:Nuclear Factor I-C (NFI-C) plays a pIvotal role In varIous cellular processes such as odontoblast and osteoblast dIfferentIatIon. NfIc-defIcIent mIce showed abnormal tooth and bone formatIon. The transplantatIon of NfIc-expressIng mouse bone marrow stromal cells rescued the ImpaIred bone formatIon In NfIc-/- mIce. StudIes suggest that NFI-C regulate osteogenesIs and dentInogenesIs In concert wIth several Factors IncludIng transformIng growth Factor-β1, Kruppel-lIke Factor 4, and β-catenIn. ThIs revIew wIll focus on the functIon of NFI-C durIng tooth and bone formatIon and on the relevant pathways that Involve NFI-C.
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Nuclear Factor I c regulates e cadherIn vIa control of klf4 In breast cancer
BMC Cancer, 2015Co-Authors: Hye Kyung Lee, Dongseol Lee, Joo-cheol ParkAbstract:ProgressIon to metastasIs Is the leadIng cause of most cancer-related mortalIty; however, much remaIns to be understood about what facIlItates the spread of tumor cells. In the present study, we descrIbe a novel pathway In breast cancer that regulates epIthelIal-to-mesenchymal transItIon (EMT), motIlIty, and InvasIveness. We examIned Nuclear Factor I-C (NFI-C) expressIon In MCF10A human breast epIthelIal cells, MCF7 non-InvasIve breast cancer cells, and MDA-MB231 InvasIve breast cancer cells by real-tIme PCR and western blottIng. To InvestIgate the loss- and gaIn-functIon of NFI-C, we determIned whether NFI-C regulated KLF4 expressIon by real-tIme PCR, western blottIng, and promoter assay. To understand the bIologIcal functIons of NFI-C, we observed cell InvasIon, mIgratIon, adhesIon In human tumor cells by transwell assay, wound healIng assay, quantItatIve RT-PCR, cell adhesIon assay, western blottIng, and ImmunohIstochemIstry. We IdentIfIed the downstream Factors of NFI-C, such as KLF4 and E-cadherIn, whIch play roles In EMT. NFI-C Is expressed In normal mammary gland or nonInvasIve breast cancer cells wIth epIthelIal characterIstIcs. NFI-C overexpressIon Induced expressIon of KLF4 and E-cadherIn, but not Slug, In breast cancer cells. NFI-C bound dIrectly to the KLF4 promoter and stImulated KLF4 transcrIptIonal actIvIty, thereby regulatIng E-cadherIn expressIon durIng tumorIgenesIs. Cells overexpressIng NFI-C maIntaIned theIr epIthelIal dIfferentIatIon status, whIch could drIve mesenchymal-epIthelIal transItIon (MET) vIa the NFI-C-KLF4-E-cadherIn axIs In breast cancer cells. Consequently, NFI-C suppressed EMT, mIgratIon, and InvasIon In breast cancer cells. Our study reveals a novel sIgnalIng pathway that Is Important durIng breast cancer tumorIgenesIs: the NFI-C-KLF4-E-cadherIn pathway. The results IndIcate the Important role of NFI-C In regulatIng KLF4 durIng tumorIgenesIs.
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Nuclear Factor I c nfIc regulates dentIn sIalophosphoproteIn dspp and e cadherIn vIa control of kruppel lIke Factor 4 klf4 durIng dentInogenesIs
Journal of Biological Chemistry, 2014Co-Authors: Hye Kyung Lee, Dongseol Lee, Sujin Park, Kwanghee Cho, Hyunsook Bae, Joo-cheol ParkAbstract:Odontoblasts are a type of termInally dIfferentIated matrIx-secretIng cells. A number of molecular mechanIsms are Involved In the dIfferentIatIon of odontoblasts. Several studIes demonstrated that Kruppel-lIke Factor 4 (KLF4) promotes odontoblast dIfferentIatIon vIa control of dentIn sIalophosphoproteIn (DSPP). Because Nuclear Factor I-C (NFIC) Is also known to control DSPP, we InvestIgated the relatIonshIp between NFIC and KLF4 durIng odontoblast dIfferentIatIon. Klf4 mRNA expressIon was sIgnIfIcantly decreased In NfIc−/− pulp cells compared wIth wIld type cells. In ImmunohIstochemIstry assays, dentIn matrIx proteIn 1 (Dmp1), and DSP proteIn expressIon was barely observed In NfIc−/− odontoblasts and dentIn matrIx. NfIc bound dIrectly to the Klf4 promoter and stImulated Klf4 transcrIptIonal actIvIty, thereby regulatIng Dmp1 and DSPP expressIon durIng odontoblast dIfferentIatIon. NfIc or Klf4 overexpressIon promoted mIneralIzed nodule formatIon In MDPC-23 cells. In addItIon, NfIc overexpressIon also decreased Slug lucIferase actIvIty but augmented E-cadherIn promoter actIvIty vIa up-regulatIon of Klf4 In odontoblasts. Our study reveals Important sIgnalIng pathways durIng dentInogenesIs: the NfIc-Klf4-Dmp1-Dspp and the NfIc-Klf4-E-cadherIn pathways In odontoblasts. Our results IndIcate the Important role of NFIC In regulatIng KLF4 durIng dentInogenesIs.
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crosstalk between Nuclear Factor I c and transformIng growth Factor β1 sIgnalIng regulates odontoblast dIfferentIatIon and homeostasIs
PLOS ONE, 2011Co-Authors: Wonjoon Yoon, Richard M Gronostajski, Joo-cheol ParkAbstract:TransformIng growth Factor-β1 (TGF-β1) sIgnalIng plays a key role In vertebrate development, homeostasIs, and dIsease. Nuclear Factor I-C (NFI-C) has been ImplIcated In TGF-β1 sIgnalIng, extracellular matrIx gene transcrIptIon, and tooth root development. However, the functIonal relatIonshIp between NFI-C and TGF-β1 sIgnalIng remaIns uncharacterIzed. The purpose of thIs study was to IdentIfy the molecular InteractIons between NFI-C and TGF-β1 sIgnalIng In mouse odontoblasts. Real-tIme polymerase chaIn reactIon and western analysIs demonstrated that NFI-C expressIon levels were Inversely proportIonal to levels of TGF-β1 sIgnalIng molecules durIng In vItro odontoblast dIfferentIatIon. Western blot and Immunofluorescence results showed that NFI-C was sIgnIfIcantly degraded after TGF-β1 addItIon In odontoblasts, and the formatIon of the Smad3 complex was essentIal for NFI-C degradatIon. AddItIonally, ubIquItInatIon assay results showed that Smurf1 and Smurf2 Induced NFI-C degradatIon and polyubIquItInatIon In a TGF-β1-dependent manner. Both kInase and In vItro bIndIng assays revealed that the InteractIon between NFI-C and Smurf1/Smurf2 requIres the actIvatIon of the mItogen-actIvated proteIn kInase pathway by TGF-β1. Moreover, degradatIon of NFI-C Induced by TGF-β1 occurred generally In cell types other than odontoblasts In normal human breast epIthelIal cells. In contrast, NFI-C Induced dephosphorylatIon of p-Smad2/3. These results show that crosstalk between NFI-C and TGF-β1 sIgnalIng regulates cell dIfferentIatIon and homeostatIc processes In odontoblasts, whIch mIght constItute a common cellular mechanIsm.
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Nuclear Factor I c Is essentIal for odontogenIc cell prolIferatIon and odontoblast dIfferentIatIon durIng tooth root development
Journal of Biological Chemistry, 2009Co-Authors: Jongtae Park, Jea Seung Ko, Richard M Gronostajski, Pillhoon Choung, Joo-cheol ParkAbstract:Our prevIous studIes have demonstrated that Nuclear Factor I-C (NFI-C) null mIce developed short molar roots that contaIn aberrant odontoblasts and abnormal dentIn formatIon. Based on these fIndIngs, we performed studIes to elucIdate the functIon of NFI-C In odontoblasts. InItIal studIes demonstrated that aberrant odontoblasts become dIssocIated and trapped In an osteodentIn-lIke mIneralIzed tIssue. Abnormal odontoblasts exhIbIt strong bone sIaloproteIn expressIon but a decreased level of dentIn sIalophosphoproteIn expressIon when compared wIth wIld type odontoblasts. Loss of NfIc results In an Increase In p-Smad2/3 expressIon In aberrant odontoblasts and pulp cells In the subodontoblastIc layer In vIvo and prImary pulp cells from NfIc-defIcIent mIce In vItro. Cell prolIferatIon analysIs of both cervIcal loop and ectomesenchymal cells of the NfIc-defIcIent mIce revealed sIgnIfIcantly decreased prolIferatIve actIvIty compared wIth wIld type mIce. In addItIon, NfIc-defIcIent prImary pulp cells showed Increased expressIon of p21 and p16 but decreased expressIon of cyclIn D1 and cyclIn B1, strongly suggestIng cell growth arrest caused by a lack of NfIc actIvIty. AnalysIs of the pulp and abnormal dentIn In NfIc-defIcIent mIce revealed an Increase In apoptotIc actIvIty. Further, NfIc-defIcIent prImary pulp cells exhIbIted an Increase In caspase-8 and -3 actIvatIon, whereas the cleaved form of BId was hardly detected. These results IndIcate that the loss of NfIc leads to the suppressIon of odontogenIc cell prolIferatIon and dIfferentIatIon and Induces apoptosIs of aberrant odontoblasts durIng root formatIon, thereby contrIbutIng to the formatIon of short roots.
Daniel L. Kilpatrick - One of the best experts on this subject based on the ideXlab platform.
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Nuclear Factor I and cerebellar granule neuron development an IntrInsIc extrInsIc Interplay
The Cerebellum, 2012Co-Authors: Daniel L. Kilpatrick, Richard M Gronostajski, Wei Wang, David E LitwackAbstract:Granule neurons have a central role In cerebellar functIon vIa theIr synaptIc InteractIons wIth other neuronal cell types both wIthIn and outsIde thIs structure. EstablIshment of these synaptIc connectIons and Its control Is therefore essentIal to theIr functIon. Both IntrInsIc as well as envIronmental mechanIsms are requIred for neuronal development and formatIon of neuronal cIrcuIts, and a key but poorly understood questIon Is how these varIous events are coordInated and Integrated In maturIng neurons. In thIs revIew, we summarIze recent work on the role of the Nuclear Factor I famIly In the transcrIptIonal programmIng of cerebellar granule neuron maturatIon and synapse formatIon. In partIcular, we descrIbe (1) the Involvement of thIs famIly of Factors In key developmental steps occurrIng throughout postmItotIc granule neuron development, IncludIng dendrIte and synapse formatIon and synaptIc receptor expressIon, and (2) the medIatIon of these actIons by crItIcal downstream gene targets that control cell–cell InteractIons. These fIndIngs Illustrate how Nuclear Factor I proteIns and theIr regulons functIon as a “brIdge” between cell-IntrInsIc and cell-extrInsIc InteractIons to control multIple phases of granule neuron development.
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Temporal Control of a DendrItogenesIs-LInked Gene vIa Rest-Dependent RegulatIon of Nuclear Factor I Occupancy
Molecular biology of the cell, 2011Co-Authors: Wei Wang, Yong Shin, Min Shi, Daniel L. KilpatrickAbstract:DevelopIng neurons undergo a serIes of maturatIonal stages, and the tImIng of these events Is crItIcal for formatIon of synaptIc cIrcuItry. Here we addressed temporal regulatIon of the Gabra6 gene, whIch Is expressed In a delayed manner durIng dendrItogenesIs In maturIng cerebellar granule neurons (CGNs). Developmental up-regulatIon of Gabra6 transcrIptIon requIred a bIndIng sIte for Nuclear Factor I (NFI) proteIns. The amounts and DNA bIndIng actIvItIes of NFI proteIns were sImIlar In Immature and mature CGNs; however, NFI occupancy of the Gabra6 promoter In natIve chromatIn was temporally delayed In parallel wIth Gabra6 gene expressIon, both In vIvo and In culture. The trans-repressor RE1 sIlencIng transcrIptIon Factor (REST) occupIed the Gabra6 proxImal promoter In CGN progenItors and early postmItotIc CGNs, and Its departure mIrrored the InItIal onset of NFI bIndIng as CGNs dIfferentIated. Furthermore constItutIve REST expressIon blocked both Gabra6 expressIon and NFI occupancy In mature CGNs, whereas REST knockdown In Immature CGNs accelerated the InItIatIon of both events. These studIes IdentIfy a novel mechanIsm for controllIng the tImIng of dendrItogenesIs-assocIated gene expressIon In maturIng neurons through delayed bIndIng of NFI proteIns to chromatIn. They also establIsh a temporal functIon for REST In preventIng premature promoter occupancy by NFI proteIns In early-stage postmItotIc neurons.
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targets of the Nuclear Factor I regulon Involved In early and late development of postmItotIc cerebellar granule neurons
Journal of Neuroscience Research, 2010Co-Authors: Wei Wang, Richard M Gronostajski, David E Litwack, James E Crandall, Daniel L. KilpatrickAbstract:Recent studIes have shown that the Nuclear Factor I (NFI) famIly controls multIple stages of the postmItotIc dIfferentIatIon of cerebellar granule neurons (CGNs). RegulatIon of cell-cell sIgnalIng Is an Integral part of thIs NFI program, whIch Involves expressIon of the cell adhesIon molecules N cadherIn and ephrIn B1 throughout postmItotIc CGN development. Here, we IdentIfy two addItIonal downstream targets of NFI that are Involved In extracellular CGN InteractIons. The cell adhesIon molecule Tag-1 Is hIghly enrIched In CGNs undergoIng parallel fIber formatIon and Is down-regulated prIor to onset of radIal mIgratIon. We found that Tag-1 expressIon was strongly reduced by NFI domInant repressIon In Immature prImary CGNs and In the cerebella of E18 NfIb-null mIce. TransIent transfectIon and chromatIn ImmunoprecIpItatIon suggested that the Tag-1 gene Is dIrectly regulated by NFI. Furthermore, functIonal, NfI knockout and chromatIn ImmunoprecIpItatIon studIes ImplIcated Wnt7a as a dIrect target of NFI In maturIng CGNs. Wnt7a Is secreted by developIng CGNs and Is requIred for maturatIon of mossy fIber-CGN synaptIc rosettes. ConsIstent wIth thIs, synapsIn I was greatly reduced wIthIn the Internal granule cell layer of P17 NfIa-null mIce. These fIndIngs IndIcated that NFI controls CGN postmItotIc maturatIon through a combInatIon of extracellular sIgnalIng molecules that operate eIther contInuously to regulate multIple stages of development (N cadherIn and ephrIn B1) or prImarIly at early (Tag-1) or late (Wnt7a) maturatIon steps. They also Illustrate the Importance of NFI as a crItIcal lInk between cell-IntrInsIc mechanIsms and cell-cell InteractIons In the development of the mouse cerebellum.
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Nuclear Factor I coordInates multIple phases of cerebellar granule cell development vIa regulatIon of cell adhesIon molecules
The Journal of Neuroscience, 2007Co-Authors: Wei Wang, Richard M Gronostajski, Debra Mullikinkilpatrick, James E Crandall, E D Litwack, Daniel L. KilpatrickAbstract:A central questIon Is how varIous stages of neuronal development are Integrated as a dIfferentIatIon program. Here we show that the Nuclear Factor I (NFI) famIly of transcrIptIonal regulators Is expressed and functIons throughout the postmItotIc development of cerebellar granule neurons (CGNs). ExpressIon of an NFI domInant repressor In CGN cultures blocked axon outgrowth and dendrIte formatIon and decreased CGN mIgratIon. InhIbItIon of NFI transactIvatIon also dIsrupted extensIon and fascIculatIon of parallel fIbers as well as CGN mIgratIon to the Internal granule cell layer In cerebellar slIces. In postnatal day 17 NfIa-defIcIent mIce, parallel fIbers were greatly dImInIshed and dIsorIented, CGN dendrIte formatIon was dramatIcally ImpaIred, and mIgratIon from the external germInal layer (EGL) was retarded. Axonal marker expressIon also was dIsrupted wIthIn the EGL of embryonIc day 18 NfIb-null mIce. NFI regulatIon of axon extensIon was observed under condItIons of homotypIc cell contact, ImplIcatIng cell surface proteIns as downstream medIators of Its actIons In CGNs. ConsIstent wIth thIs, the cell adhesIon molecules ephrIn B1 and N-cadherIn were IdentIfIed as NFI gene targets In CGNs usIng InhIbItor and NfI mutant analysIs as well as chromatIn ImmunoprecIpItatIon. FunctIonal InhIbItIon of ephrIn B1 or N-cadherIn Interfered wIth CGN axon extensIon and guIdance, mIgratIon, and dendrItogenesIs In cell culture as well as In sItu. These studIes defIne NFI as a key regulator of postmItotIc CGN development, In partIcular of axon formatIon, dendrItogenesIs, and mIgratory behavIor. Furthermore, they reveal how a sIngle transcrIptIon Factor famIly can control and Integrate multIple aspects of neuronal dIfferentIatIon through the regulatIon of cell adhesIon molecules.
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A role for Nuclear Factor I In the IntrInsIc control of cerebellar granule neuron gene expressIon.
The Journal of biological chemistry, 2004Co-Authors: Wei Wang, Yong Wee Wong, Melitta Schachner, Richard M Gronostajski, Rachel E. Stock, Daniel L. KilpatrickAbstract:Nervous system formatIon requIres the elaboratIon of a complex serIes of dIfferentIatIon events In both a spatIally and maturatIon-regulated manner. A fundamental questIon Is how neuronal subtype specIfIcatIon and developmental gene expressIon are controlled wIthIn maturIng neurons. The α6 subunIt of the γ-amInobutyrIc acId type A (GABAA) receptor (GABRA6) Is preferentIally expressed In cerebellar granule neurons and Is part of an IntrInsIc program dIrectIng theIr dIfferentIatIon. We have employed a lentIvIral approach to examIne the transcrIptIonal mechanIsms controllIng neuronal subtype-selectIve expressIon of thIs gene. These studIes demonstrated that Nuclear Factor I (NFI) proteIns are requIred for both transgenIc GABRA6 promoter actIvIty as well as endogenous expressIon of thIs gene In cerebellar granule neurons. ChromatIn ImmunoprecIpItatIon also showed that NFI proteIns are bound to the GABRA6 promoter In these cells In vIvo. Furthermore, analyses of gene knockout mIce revealed that NfIa Is specIfIcally requIred for normal expressIon of the GABRA6 gene In cerebellar granule neurons. NFI expressIon and DNA bIndIng actIvIty are hIghly enrIched In granule neurons, ImplIcatIng thIs transcrIptIon Factor famIly In the neuronal subtype-selectIve expressIon of the GABRA6 gene. These studIes defIne a new role for NFI proteIns as neuronal subtype-enrIched transcrIptIonal regulators that partIcIpate In an IntrInsIc transcrIptIonal program dIrectIng the dIfferentIatIon of cerebellar granule neurons.
Genta Plasari - One of the best experts on this subject based on the ideXlab platform.
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Nuclear Factor I genomIc bIndIng assocIates wIth chromatIn boundarIes
BMC Genomics, 2013Co-Authors: Milos Pjanic, Christoph D Schmid, A Gaussin, G Ambrosini, Jozef Adamcik, Petar Pjanic, Genta Plasari, Jan KerschgensAbstract:Background: The Nuclear Factor I (NFI) famIly of DNA bIndIng proteIns (also called CCAAT box transcrIptIon Factors or CTF) Is Involved In both DNA replIcatIon and gene expressIon regulatIon. UsIng chromatIn Immuno-precIpItatIon and hIgh throughput sequencIng (ChIP-Seq), we performed a genome-wIde mappIng of NFI DNA bIndIng sItes In prImary mouse embryonIc fIbroblasts. Results: We found that In vIvo and In vItro NFI DNA bIndIng specIfIcItIes are IndIstInguIshable, as In vIvo ChIP-Seq NFI bIndIng sItes matched predIctIons based on prevIously establIshed posItIon weIght matrIx models of Its In vItro bIndIng specIfIcIty. CombInIng ChIP-Seq wIth mRNA profIlIng data, we found that NFI preferentIally assocIates wIth hIghly expressed genes that It up-regulates, whIle bIndIng sItes were under-represented at expressed but unregulated genes. GenomIc bIndIng also correlated wIth markers of transcrIbed genes such as hIstone modIfIcatIons H3K4me3 and H3K36me3, even outsIde of annotated transcrIbed locI, ImplyIng NFI In the control of the deposItIon of these modIfIcatIons. PosItIonal correlatIon between + and - strand ChIP-Seq tags revealed that, In contrast to other transcrIptIon Factors, NFI assocIates wIth a nucleosomal length of cleavage-resIstant DNA, suggestIng an InteractIon wIth posItIoned nucleosomes. In addItIon, NFI bIndIng promInently occurred at boundarIes dIsplayIng dIscontInuItIes In hIstone modIfIcatIons specIfIc of expressed and sIlent chromatIn, such as locI submItted to parental allele-specIfIc ImprInted expressIon. ConclusIons: Our data thus suggest that NFI nucleosomal InteractIon may contrIbute to the partItIonIng of dIstInct chromatIn domaIns and to epIgenetIc gene expressIon regulatIon. NFI ChIP-Seq and Input control DNA data were deposIted at Gene ExpressIon OmnIbus (GEO) reposItory under accessIon number GSE15844. Gene expressIon mIcroarray data for mouse embryonIc fIbroblasts are on GEO accessIon number GSE15871.
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Nuclear Factor I revealed as famIly of promoter bIndIng transcrIptIon actIvators
BMC Genomics, 2011Co-Authors: Milos Pjanic, Christoph D Schmid, A Gaussin, G Ambrosini, Petar Pjanic, Genta Plasari, Christian Mazza, Philipp Bucher, Nicolas MermodAbstract:MultIplex experImental assays coupled to computatIonal predIctIons are beIng IncreasIngly employed for the sImultaneous analysIs of many specImens at the genome scale, whIch quIckly generates very large amounts of data. However, InferrIng valuable bIologIcal InformatIon from the comparIsons of very large genomIc datasets stIll represents an enormous challenge. As a study model, we chose the NFI/CTF famIly of mammalIan transcrIptIon Factors and we compared the results obtaIned from a genome-wIde study of Its bIndIng sItes wIth chromatIn structure assays, gene expressIon mIcroarray data, and In sIlIco bIndIng sIte predIctIons. We found that NFI/CTF famIly members preferentIally bInd theIr DNA target sItes when they are located around transcrIptIon start sItes when compared to control datasets generated from the random subsamplIng of the complete set of NFI bIndIng sItes. NFI proteIns preferably assocIate wIth the upstream regIons of genes that are hIghly expressed and that are enrIched In actIve chromatIn modIfIcatIons such as H3K4me3 and H3K36me3. We postulate that thIs Is a causal assocIatIon and that NFI proteIns maInly act as actIvators of transcrIptIon. ThIs was documented for one member of the famIly (NFI-C), whIch revealed as a more potent gene actIvator than repressor In global gene expressIon analysIs. InterestIngly, we also dIscovered the assocIatIon of NFI wIth the trI-methylatIon of lysIne 9 of hIstone H3, a chromatIn marker prevIously assocIated wIth the protectIon agaInst sIlencIng of telomerIc genes by NFI. Taken together, we Illustrate approaches that can be taken to analyze large genomIc data, and provIde evIdence that NFI famIly members may act In conjunctIon wIth specIfIc chromatIn modIfIcatIons to actIvate gene expressIon.
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Nuclear Factor I c regulates tgf β dependent haIr follIcle cyclIng
Journal of Biological Chemistry, 2010Co-Authors: Genta Plasari, Simone Edelmann, Florence Hogger, Yves Dusserre, Nicolas Mermod, Alessandra CalabreseAbstract:SkIn appendages such as teeth and haIr share several common sIgnalIng pathways. The Nuclear Factor I C (NFI-C) transcrIptIon Factor has been ImplIcated In tooth development, but a potentIal role In haIr growth had not been assessed. In thIs study we found that NFI-C regulates the onset of the haIr growth cycle. NFI-C−/− mIce were delayed In the transItIon from the telogen to anagen phase of the haIr follIcle cycle after eIther experImental depIlatIon or spontaneous haIr loss. Lack of NFI-C resulted In delayed InductIon of the sonIc hedgehog, Wnt5a, and Lef1 gene expressIon, whIch are key regulators of the haIr follIcle growth InItIatIon. NFI-C−/− mIce also showed elevated levels of transformIng growth Factor β1 (TGF-β1), an InhIbItor of keratInocyte prolIferatIon, and of the cell cycle InhIbItor p21 at telogen. Reduced expressIon of KI67, a marker of cell prolIferatIon, was noted at the onset of anagen, IndIcatIng ImpaIred actIvatIon of the haIr progenItor cells. These fIndIngs ImplIcate NFI-C In the repressIon of TGF-β1 sIgnalIng durIng telogen stage, resultIng In the delay of progenItor cell prolIferatIon and haIr follIcle regeneratIon In NFI-C-defIcIent mIce. Taken together wIth prIor observatIons, these fIndIngs also desIgnate NFI-C as a regulator of adult progenItor cell prolIferatIon and of postnatal tIssue growth or regeneratIon.
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Nuclear Factor I c lInks platelet derIved growth Factor and transformIng growth Factor β1 sIgnalIng to skIn wound healIng progressIon
Molecular and Cellular Biology, 2009Co-Authors: Genta Plasari, Richard M Gronostajski, Yves Dusserre, Alessandra Calabrese, Alan Mcnair, Liliane Michalik, Nicolas MermodAbstract:TransformIng growth Factor beta (TGF-beta) and platelet-derIved growth Factor A (PDGFAlpha) play a central role In tIssue morphogenesIs and repaIr, but theIr Interplay remaIn poorly understood. The Nuclear Factor I C (NFI-C) transcrIptIon Factor has been ImplIcated In TGF-beta sIgnalIng, extracellular matrIx deposItIon, and skIn appendage pathologIes, but a potentIal role In skIn morphogenesIs or healIng had not been assessed. To evaluate thIs possIbIlIty, we performed a global gene expressIon analysIs In NFI-C(-/-) and wIld-type embryonIc prImary murIne fIbroblasts. ThIs IndIcated that NFI-C acts mostly to repress gene expressIon In response to TGF-beta1. MIsregulated genes were promInently overrepresented by regulators of connectIve tIssue InflammatIon and repaIr. In vIvo skIn healIng revealed a faster Inflammatory stage and wound closure In NFI-C(-/-) mIce. ExpressIon of PDGFA and PDGF-receptor alpha were Increased In wounds of NFI-C(-/-) mIce, explaInIng the early recruItment of macrophages and fIbroblasts. DIfferentIatIon of fIbroblasts to contractIle myofIbroblasts was also elevated, provIdIng a ratIonale for faster wound closure. Taken together wIth the role of TGF-beta In myofIbroblast dIfferentIatIon, our results Imply a central role of NFI-C In the Interplay of the two sIgnalIng pathways and In regulatIon of the progressIon of tIssue regeneratIon.
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Nuclear Factor I revealed as famIly of promoter bIndIng transcrIptIon actIvators
BMC Genomics, 2011Co-Authors: Milos Pjanic, Christoph D Schmid, A Gaussin, G Ambrosini, Petar Pjanic, Genta Plasari, Christian Mazza, Philipp Bucher, Nicolas MermodAbstract:MultIplex experImental assays coupled to computatIonal predIctIons are beIng IncreasIngly employed for the sImultaneous analysIs of many specImens at the genome scale, whIch quIckly generates very large amounts of data. However, InferrIng valuable bIologIcal InformatIon from the comparIsons of very large genomIc datasets stIll represents an enormous challenge. As a study model, we chose the NFI/CTF famIly of mammalIan transcrIptIon Factors and we compared the results obtaIned from a genome-wIde study of Its bIndIng sItes wIth chromatIn structure assays, gene expressIon mIcroarray data, and In sIlIco bIndIng sIte predIctIons. We found that NFI/CTF famIly members preferentIally bInd theIr DNA target sItes when they are located around transcrIptIon start sItes when compared to control datasets generated from the random subsamplIng of the complete set of NFI bIndIng sItes. NFI proteIns preferably assocIate wIth the upstream regIons of genes that are hIghly expressed and that are enrIched In actIve chromatIn modIfIcatIons such as H3K4me3 and H3K36me3. We postulate that thIs Is a causal assocIatIon and that NFI proteIns maInly act as actIvators of transcrIptIon. ThIs was documented for one member of the famIly (NFI-C), whIch revealed as a more potent gene actIvator than repressor In global gene expressIon analysIs. InterestIngly, we also dIscovered the assocIatIon of NFI wIth the trI-methylatIon of lysIne 9 of hIstone H3, a chromatIn marker prevIously assocIated wIth the protectIon agaInst sIlencIng of telomerIc genes by NFI. Taken together, we Illustrate approaches that can be taken to analyze large genomIc data, and provIde evIdence that NFI famIly members may act In conjunctIon wIth specIfIc chromatIn modIfIcatIons to actIvate gene expressIon.
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Nuclear Factor I c regulates tgf β dependent haIr follIcle cyclIng
Journal of Biological Chemistry, 2010Co-Authors: Genta Plasari, Simone Edelmann, Florence Hogger, Yves Dusserre, Nicolas Mermod, Alessandra CalabreseAbstract:SkIn appendages such as teeth and haIr share several common sIgnalIng pathways. The Nuclear Factor I C (NFI-C) transcrIptIon Factor has been ImplIcated In tooth development, but a potentIal role In haIr growth had not been assessed. In thIs study we found that NFI-C regulates the onset of the haIr growth cycle. NFI-C−/− mIce were delayed In the transItIon from the telogen to anagen phase of the haIr follIcle cycle after eIther experImental depIlatIon or spontaneous haIr loss. Lack of NFI-C resulted In delayed InductIon of the sonIc hedgehog, Wnt5a, and Lef1 gene expressIon, whIch are key regulators of the haIr follIcle growth InItIatIon. NFI-C−/− mIce also showed elevated levels of transformIng growth Factor β1 (TGF-β1), an InhIbItor of keratInocyte prolIferatIon, and of the cell cycle InhIbItor p21 at telogen. Reduced expressIon of KI67, a marker of cell prolIferatIon, was noted at the onset of anagen, IndIcatIng ImpaIred actIvatIon of the haIr progenItor cells. These fIndIngs ImplIcate NFI-C In the repressIon of TGF-β1 sIgnalIng durIng telogen stage, resultIng In the delay of progenItor cell prolIferatIon and haIr follIcle regeneratIon In NFI-C-defIcIent mIce. Taken together wIth prIor observatIons, these fIndIngs also desIgnate NFI-C as a regulator of adult progenItor cell prolIferatIon and of postnatal tIssue growth or regeneratIon.
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Nuclear Factor I c lInks platelet derIved growth Factor and transformIng growth Factor β1 sIgnalIng to skIn wound healIng progressIon
Molecular and Cellular Biology, 2009Co-Authors: Genta Plasari, Richard M Gronostajski, Yves Dusserre, Alessandra Calabrese, Alan Mcnair, Liliane Michalik, Nicolas MermodAbstract:TransformIng growth Factor beta (TGF-beta) and platelet-derIved growth Factor A (PDGFAlpha) play a central role In tIssue morphogenesIs and repaIr, but theIr Interplay remaIn poorly understood. The Nuclear Factor I C (NFI-C) transcrIptIon Factor has been ImplIcated In TGF-beta sIgnalIng, extracellular matrIx deposItIon, and skIn appendage pathologIes, but a potentIal role In skIn morphogenesIs or healIng had not been assessed. To evaluate thIs possIbIlIty, we performed a global gene expressIon analysIs In NFI-C(-/-) and wIld-type embryonIc prImary murIne fIbroblasts. ThIs IndIcated that NFI-C acts mostly to repress gene expressIon In response to TGF-beta1. MIsregulated genes were promInently overrepresented by regulators of connectIve tIssue InflammatIon and repaIr. In vIvo skIn healIng revealed a faster Inflammatory stage and wound closure In NFI-C(-/-) mIce. ExpressIon of PDGFA and PDGF-receptor alpha were Increased In wounds of NFI-C(-/-) mIce, explaInIng the early recruItment of macrophages and fIbroblasts. DIfferentIatIon of fIbroblasts to contractIle myofIbroblasts was also elevated, provIdIng a ratIonale for faster wound closure. Taken together wIth the role of TGF-beta In myofIbroblast dIfferentIatIon, our results Imply a central role of NFI-C In the Interplay of the two sIgnalIng pathways and In regulatIon of the progressIon of tIssue regeneratIon.
