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1.
Diagn Pathol ; 17(1): 64, 2022 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-35941667

RESUMO

BACKGROUND: Follicular dendritic cell sarcoma (FDCS) is a rare neoplasm of mesenchymal origin. FDCS of gastrointestinal tract (GI) are exceedingly uncommon. CASE PRESENTATION: We report the first case of classic type FDCS in a 34-year-old male with Birt-Hogg-Dubé syndrome, which presented as a mass at the ileo-cecal junction. He received no further treatment after resection and remained disease free for 3.5 years. We further analyze and review the clinical and pathologic findings of 33 cases of GI tract FDCS reported in the literature. CONCLUSIONS: There are two distinct subtypes of FDCS in the GI tract: the classic type occurs in relatively younger patients (mean = 45.3 years) without Epstein-Barr virus (EBV) association, and behaves more aggressively; the inflammatory subtype presents as colonic polypoid tumor in older patients (mean = 60.7 years) and is EBV positive. The clinical outcome in the latter group appears favorable although mortality rate is not necessarily low.


Assuntos
Sarcoma de Células Dendríticas Foliculares , Infecções por Vírus Epstein-Barr , Adulto , Idoso , Humanos , Masculino , Sarcoma de Células Dendríticas Foliculares/patologia , Intervalo Livre de Doença , Trato Gastrointestinal/patologia , Herpesvirus Humano 4/genética
3.
Ann Transl Med ; 10(6): 316, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35434041

RESUMO

Background: Functional constipation (FC) is a common gastrointestinal (GI) disorder characterized by symptoms of constipation without a clear physiologic or anatomic cause. Gut microbiome dysbiosis has been postulated to be a factor in the development of FC, and treatment with probiotic regimens, including strains of Lactobacillus plantarum (L. plantarum), has demonstrated efficacy in managing symptoms. To further understand the role of L. plantarum in GI health, we conducted an animal study and a randomized, double-blind, placebo-controlled clinical trial to evaluate the effect of a specific sub-strain, Lp3a, on FC. Methods: For the animal study, male Kunming mice were treated with doses of L. plantarum Lp3a ranging from 0.67 to 2.00 g/kg or an equivalent amount of placebo for 15 days prior to the induction of constipation via 20 mL/kg of 25% diphenoxylate solution. GI motility parameters including intestinal motion and stool amount were then assessed. In the human study, 120 patients with FC were randomized to treatment [L. plantarum Lp3a; 2×1.0×1010 (colony forming units; CFU) ×7 days] or control groups (n=60 each). The primary endpoint was survey information on FC signs/symptoms. Participants and observers were blinded to group allocation. A subset of 20 Lp3a treated patients underwent pre- and post-treatment 16 s ribosomal ribonucleic acid (rRNA) gene sequencing. Whole genome sequencing (WGS) of L. plantarum Lp3a was also performed. Results: Lp3a-treated mice showed significantly improved intestinal motion, reduced time to first defecation, and increased stool amounts. Similarly, patients in the treatment group (n=59) reported significant improvements in FC signs/symptoms compared to controls (n=58; all P<0.05). Although 16 s rRNA sequencing revealed no significant variations between pre- and post-treatment samples, WGS of Lp3a itself revealed several biological pathways that may underlie the relief of FC symptoms in animals and humans, including methane and fatty acid metabolism and bile acid biosynthesis. Conclusions: We found that the use of the novel probiotic sub-strain, L. plantarum Lp3a, led to clinically significant improvements in FC in both mice and humans, and identified the potential biological mechanisms underlying this activity.

4.
Polymers (Basel) ; 14(7)2022 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-35406358

RESUMO

The global water crisis is becoming more and more serious, and solar steam generation has recently been investigated for clean water production and wastewater treatment. However, the efficiency of solar vapor transfer is still low. It is a great challenge to find photothermal materials which simultaneously have high energy transfer efficiency, facile production, and are low cost. To address this, we propose a method which is simple, low cost and suitable for large-scale preparation to fabricate the photothermal materials based on using recycled natural rubber sponge (NRS) coated with polydopamine (PDA). X-ray photoelectron spectroscopy analysis confirmed that when the PDA coated the surface of the NRS, the hydrophilicity of the sponge was significantly improved. Scanning electron microscopy characterization showed that the PDA-coated natural rubber sponge (PNRS) maintained the porous 3D skeleton of the pristine sponge. As a result, PNRS exhibits excellent photothermal properties, a very high evaporation rate of 1.35 kg m-2 h-1, and an energy transfer efficiency of 84.6% can be achieved under a light intensity of 1 sun (1 kW m-2). It is worth noting that the vapor generation of PNRS is still at a high level with 1.06 and 1.09 kg m-2 h-1 in the corrosive liquids of 1 M H2SO4 and 0.5 M NaOH, respectively. The photothermal materials based on using recycled NRS have good application prospects in seawater desalination and the purification of wastewater, which also provides a new method for the recycling of waste NRS.

5.
Am J Surg Pathol ; 44(11): 1535-1540, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32773530

RESUMO

Primary pulmonary myxoid sarcoma (PPMS) is a recently reported, exceedingly rare low-grade lung neoplasm characterized by reticular/lace-like growth of spindle to epithelioid cells embedded in an abundant myxoid matrix. Morphologically, it overlaps with a myxoid variant of angiomatoid fibrous histiocytoma (AFH) of the soft tissue. Genetically, they were both reported to harbor EWSR1-CREB1 fusion, while EWSR1-ATF1 has only been reported in AFH thus far. We report a case of primary pulmonary low-grade myxoid spindle cell tumor with morphologic and immunohistochemical features of PPMS but with an EWSR1-ATF1 fusion gene. In addition, we also encountered a case of endobronchial AFH with EWSR1-CREB1 translocation but also focal morphologic features of PPMS. These findings provide new evidence supporting the concept that PPMS and a myxoid variant of AFH represent a continuum with overlapping histologic, immunohistochemical, and genetic features.


Assuntos
Histiocitoma Fibroso Maligno/genética , Histiocitoma Fibroso Maligno/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mixossarcoma/genética , Mixossarcoma/patologia , Proteínas de Fusão Oncogênica/genética , Adulto , Humanos , Masculino , Pessoa de Meia-Idade
6.
World J Gastrointest Pathophysiol ; 11(4): 78-83, 2020 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-32587787

RESUMO

Traditional serrated adenoma was first reported by Longacre and Fenoglio-Presier in 1990. Their initial study described main features of this lesion, but the consensus diagnostic criteria were not widely adopted until recently. Traditional serrated adenoma presents with grossly protuberant configuration and pinecone-like appearance upon endoscopy. Histologically, it is characterized by ectopic crypt formation, slit-like serration, eosinophilic cytoplasm and pencillate nuclei. Although much is now known about the morphology and molecular changes, the mechanisms underlying the morphological alterations are still not fully understood. Furthermore, the origin of traditional serrated adenoma is not completely known. We review recent studies of the traditional serrated adenoma and provide an overview on current understanding of this rare entity.

7.
Int J Surg Pathol ; 27(3): 328-335, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30270691

RESUMO

Sclerosing rhabdomyosarcoma (RMS) is a rare subtype of RMS with unique prominent stromal hyalinization and a pseudovascular architecture. It overlaps morphologically with spindle cell RMS and poses both diagnostic and therapeutic challenges because of its rarity and aggressive clinical course. In this article, we report a case of sclerosing RMS arising from a prior craniotomy site, which demonstrated both sclerosing and spindle cell components. A literature review of RMS with sclerosing morphology identified 122 cases. Our review documents the following: sclerosing RMS occurs in both childhood and adult populations, has a predilection for the head and neck areas, and has a worse prognosis in adults. Sclerosing RMS harbors a high frequency of MYOD1 mutations, conferring a poor clinical outcome. Sclerosing RMS and spindle RMS likely represent a morphologic spectrum of one entity.


Assuntos
Craniotomia/efeitos adversos , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias Musculares/patologia , Rabdomiossarcoma/patologia , Tela Subcutânea/patologia , Aneurisma Roto/etiologia , Aneurisma Roto/cirurgia , Biópsia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Quimiorradioterapia Adjuvante , Diagnóstico Diferencial , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/etiologia , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Aneurisma Intracraniano/complicações , Masculino , Pessoa de Meia-Idade , Neoplasias Musculares/diagnóstico por imagem , Neoplasias Musculares/etiologia , Neoplasias Musculares/terapia , Rabdomiossarcoma/diagnóstico por imagem , Rabdomiossarcoma/etiologia , Rabdomiossarcoma/terapia , Couro Cabeludo , Esclerose , Tela Subcutânea/diagnóstico por imagem , Tomografia Computadorizada por Raios X
8.
J Neurochem ; 141(3): 347-357, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28144959

RESUMO

The Notch signaling pathway controls cell fate decision, proliferation, and other biological functions in both vertebrates and invertebrates. Precise regulation of the canonical Notch pathway ensures robustness of the signal throughout development and adult tissue homeostasis. Aberrant Notch signaling results in profound developmental defects and is linked to many human diseases. In this study, we identified the Atrophin family protein RERE (also called Atro2) as a positive regulator of Notch target Hes genes in the developing vertebrate spinal cord. Prior studies have shown that during early embryogenesis in mouse and zebrafish, deficit of RERE causes various patterning defects in multiple organs including the neural tube. Here, we detected the expression of RERE in the developing chick spinal cord, and found that normal RERE activity is needed for proper neural progenitor proliferation and neuronal differentiation possibly by affecting Notch-mediated Hes expression. In mammalian cells, RERE co-immunoprecipitates with CBF1 and Notch intracellular domain (NICD), and is recruited to nuclear foci formed by over-expressed NICD1. RERE is also necessary for NICD to activate the expression of Notch target genes. Our findings suggest that RERE stimulates Notch target gene expression by preventing degradation of NICD protein, thereby facilitating the assembly of a transcriptional activating complex containing NICD, CBF1/RBPjκ in vertebrate, Su(H) in Drosophila melanogaster, Lag1 in C. elegans, and other coactivators.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Receptores Notch/fisiologia , Medula Espinal/embriologia , Medula Espinal/metabolismo , Animais , Diferenciação Celular/fisiologia , Linhagem Celular , Embrião de Galinha , Eletroporação , Regulação da Expressão Gênica/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Células-Tronco Neurais , Neurônios , Ativação Transcricional , Transfecção
9.
Onco Targets Ther ; 10: 195-203, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28115854

RESUMO

OBJECTIVE: This study investigated the correlation between choline/creatine (Cho/Cr) ratios determined by multivoxel proton magnetic resonance spectroscopy (1H-MRS) and the distribution of cancer stem-like cells (CSLCs) in high-grade gliomas. PATIENTS AND METHODS: Sixteen patients with high-grade gliomas were recruited and underwent 1H-MRS examination before surgery to identify distinct tumor regions with variable Cho/Cr ratios. Using intraoperative neuronavigation, tumor tissues were accurately sampled from regions with high and low Cho/Cr ratios within each tumor. The distribution of CSLCs in samples from glioma tissue regions with different Cho/Cr ratios was quantified by neurosphere culture, immunohistochemistry, and Western blot. RESULTS: The mean neurosphere formation rate in tissues with high Cho/Cr ratios was significantly increased compared with that in low Cho/Cr ratio tissues (13.94±5.94 per 100 cells vs 8.04±3.99 per 100 cells, P<0.001). Immunohistochemistry indicated that tissues with high Cho/Cr ratios had elevated expression of CD133, nestin, and CD15, relative to low Cho/Cr ratio tissue samples (23.6%±3.8% vs 18.3%±3.3%, 25.2%±4.5% vs 19.8%±2.8%, 24.5%±3.8% vs 17.8%±2.2%, respectively; all P<0.001). Western blot demonstrated that relative CD133 and nestin protein expression in high Cho/Cr ratio regions was significantly higher than that in low Cho/Cr ratio tissue samples (0.50±0.17 vs 0.30±0.08, 0.45±0.13 vs 0.27±0.07, respectively; both P<0.001). The protein expression levels of CD133 and nestin were highly correlated with Cho/Cr ratios (r=0.897 and r=0.861, respectively). CONCLUSION: Cho/Cr ratios correlate with the distribution of CSLCs in high-grade gliomas, and this may assist in identifying foci enriched with CSLCs and thus improve the management of high-grade gliomas.

10.
PLoS Genet ; 9(4): e1003436, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23637616

RESUMO

Polycomb bodies are foci of Polycomb proteins in which different Polycomb target genes are thought to co-localize in the nucleus, looping out from their chromosomal context. We have shown previously that insulators, not Polycomb response elements (PREs), mediate associations among Polycomb Group (PcG) targets to form Polycomb bodies. Here we use live imaging and 3C interactions to show that transgenes containing PREs and endogenous PcG-regulated genes are targeted by insulator proteins to different nuclear structures depending on their state of activity. When two genes are repressed, they co-localize in Polycomb bodies. When both are active, they are targeted to transcription factories in a fashion dependent on Trithorax and enhancer specificity as well as the insulator protein CTCF. In the absence of CTCF, assembly of Polycomb bodies is essentially reduced to those representing genomic clusters of Polycomb target genes. The critical role of Trithorax suggests that stable association with a specialized transcription factory underlies the cellular memory of the active state.


Assuntos
Proteínas de Drosophila , Complexo Repressor Polycomb 1 , Núcleo Celular/genética , Proteínas de Ligação a DNA/genética , Proteínas de Drosophila/genética , Humanos , Complexo Repressor Polycomb 1/genética , Proteínas do Grupo Polycomb/genética , Elementos de Resposta
11.
PLoS Genet ; 8(9): e1002954, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23028361

RESUMO

Chromatin environments differ greatly within a eukaryotic genome, depending on expression state, chromosomal location, and nuclear position. In genomic regions characterized by high repeat content and high gene density, chromatin structure must silence transposable elements but permit expression of embedded genes. We have investigated one such region, chromosome 4 of Drosophila melanogaster. Using chromatin-immunoprecipitation followed by microarray (ChIP-chip) analysis, we examined enrichment patterns of 20 histone modifications and 25 chromosomal proteins in S2 and BG3 cells, as well as the changes in several marks resulting from mutations in key proteins. Active genes on chromosome 4 are distinct from those in euchromatin or pericentric heterochromatin: while there is a depletion of silencing marks at the transcription start sites (TSSs), HP1a and H3K9me3, but not H3K9me2, are enriched strongly over gene bodies. Intriguingly, genes on chromosome 4 are less frequently associated with paused polymerase. However, when the chromatin is altered by depleting HP1a or POF, the RNA pol II enrichment patterns of many chromosome 4 genes shift, showing a significant decrease over gene bodies but not at TSSs, accompanied by lower expression of those genes. Chromosome 4 genes have a low incidence of TRL/GAGA factor binding sites and a low T(m) downstream of the TSS, characteristics that could contribute to a low incidence of RNA polymerase pausing. Our data also indicate that EGG and POF jointly regulate H3K9 methylation and promote HP1a binding over gene bodies, while HP1a targeting and H3K9 methylation are maintained at the repeats by an independent mechanism. The HP1a-enriched, POF-associated chromatin structure over the gene bodies may represent one type of adaptation for genes embedded in repetitive DNA.


Assuntos
Proteínas Cromossômicas não Histona , Heterocromatina/genética , Histona-Lisina N-Metiltransferase , Histonas , Animais , Animais Geneticamente Modificados , Homólogo 5 da Proteína Cromobox , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Cromossomos/metabolismo , RNA Polimerases Dirigidas por DNA/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Eucromatina/metabolismo , Regulação da Expressão Gênica/genética , Heterocromatina/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Metilação , Mutação
12.
EMBO Rep ; 12(5): 428-35, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21475249

RESUMO

Ataxin-1 (ATXN1), a causative factor for spinocerebellar ataxia type 1 (SCA1), and the related Brother of ATXN1 (BOAT1) are human proteins involved in transcriptional repression. So far, little is known about which transcriptional pathways mediate the effects of ATXN1 and BOAT1. From our analyses of the properties of BOAT1 in Drosophila and of both proteins in mammalian cells, we report here that BOAT1 and ATXN1 are components of the Notch signalling pathway. In Drosophila, BOAT1 compromises the activities of Notch. In mammalian cells, both ATXN1 and BOAT1 bind to the promoter region of Hey1 and inhibit the transcriptional output of Notch through direct interactions with CBF1, a transcription factor that is crucial for the Notch pathway. Our results suggest that, in addition to their involvement in SCA1, ATXN1 and BOAT1 might participate in several Notch-controlled developmental and pathological processes.


Assuntos
Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Receptores Notch/metabolismo , Proteínas Repressoras/metabolismo , Transdução de Sinais/fisiologia , Animais , Ataxina-1 , Ataxinas , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Imunoprecipitação da Cromatina , Primers do DNA/genética , Drosophila , Proteínas de Drosophila/metabolismo , Humanos , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/metabolismo , Imunoprecipitação , Camundongos , Microscopia de Fluorescência , Plasmídeos/genética , Reação em Cadeia da Polimerase , RNA Interferente Pequeno/genética , Transdução de Sinais/genética , Técnicas do Sistema de Duplo-Híbrido
13.
Dev Neurosci ; 33(1): 1-13, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21124006

RESUMO

Drosophila Tailless(Tll) and its vertebrate homologue Tlx are conserved orphan nuclear receptors specifically expressed in the eye and the forebrain. Tll and Tlx act primarily as transcriptional repressors through their interactions with transcriptional corepressors, Atrophin family proteins, and histone-tail/chromatin-modifying factors such as lysine-specific histone demethylase 1 and histone deacetylases. The functional importance of Tll and Tlx is made apparent by the recent discovery that they are expressed in neural stem cells (NSCs) and are required for self-renewal of these cells in both Drosophila and the mouse. This review provides a snapshot of current knowledge about Tll and Tlx and their transcriptional network, which maintains NSCs in developing and adult animals.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/fisiologia , Células-Tronco Neurais/fisiologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas Repressoras/metabolismo , Transcrição Gênica , Sequência de Aminoácidos , Animais , Sistema Nervoso Central/anatomia & histologia , Sistema Nervoso Central/embriologia , Sistema Nervoso Central/crescimento & desenvolvimento , Proteínas de Drosophila/classificação , Proteínas de Drosophila/genética , Drosophila melanogaster/anatomia & histologia , Drosophila melanogaster/embriologia , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Células-Tronco Neurais/citologia , Filogenia , Receptores Citoplasmáticos e Nucleares/classificação , Receptores Citoplasmáticos e Nucleares/genética , Proteínas Repressoras/classificação , Proteínas Repressoras/genética , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos
14.
J Biomed Sci ; 17: 59, 2010 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-20663119

RESUMO

BACKGROUND: Sindbis virus (SV) is the prototype of alphaviruses which are a group of widely distributed human and animal pathogens. Heterogeneous nuclear ribonucleoprotein (hnRNP) A1 is an RNA-binding protein that shuttles between the nucleus and the cytoplasm. Our recent studies found that hnRNP A1 relocates from nucleus to cytoplasm in Sindbis virus (SV)-infected cells. hnRNP A1 binds to the 5' UTR of SV RNA and facilitates the viral RNA replication and translation. METHODS: Making use of standard molecular techniques, virology methods and an in vitro system developed by our lab to assess the role of hnRNP A1 in SV positive strand RNA synthesis. RESULTS: hnRNP A1 interacted with the genomic (G) and subgenomic (SG) RNA promoters. Knockdown of hnRNP A1 resulted in markedly decrease in the synthesis of G and SG RNA both in infected cells and in vitro. CONCLUSIONS: Our study provides the first direct evidence that hnRNP A1 actively participates in viral RNA replication and is required for the synthesis of G and SG RNA.


Assuntos
Regiões 5' não Traduzidas/genética , Citoplasma/metabolismo , Regulação Viral da Expressão Gênica/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/metabolismo , Regiões Promotoras Genéticas/genética , RNA Viral/metabolismo , Sindbis virus/genética , Transporte Ativo do Núcleo Celular/fisiologia , Animais , Northern Blotting , Western Blotting , Linhagem Celular , Embrião de Galinha , Chlorocebus aethiops , Citoplasma/fisiologia , Técnicas de Silenciamento de Genes , Ribonucleoproteína Nuclear Heterogênea A1 , RNA Interferente Pequeno/genética , RNA Viral/genética
15.
Dev Dyn ; 237(2): 393-402, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18213584

RESUMO

Proper central nervous system (CNS) function depends critically on the generation of functionally distinct neuronal types in specific and reproducible positions. The generation of neuronal diversity during CNS development involves a fine balance between dividing neural progenitors and the differentiated neuronal progeny that they produce. However, the molecular mechanisms that regulate these processes are still poorly understood. Here, we show that the Prox1 transcription factor, which is expressed transiently and specifically in spinal interneurons, plays an important role in neurogenesis. Using both gain- and loss-of-function approaches, we find that Prox1 is capable of driving neuronal precursors out of the cell cycle and can initiate limited expression of neuronal proteins. Using RNAi approaches, we show that Prox1 function is required to execute a neurogenic differentiation program downstream of Mash1 and Ngn2. Our studies demonstrate an important, spinal interneuron-specific role for Prox1 in controlling steps required for both cell-cycle withdrawal and differentiation.


Assuntos
Ciclo Celular/fisiologia , Diferenciação Celular/fisiologia , Proteínas de Homeodomínio/metabolismo , Interneurônios/fisiologia , Medula Espinal/embriologia , Proteínas Supressoras de Tumor/metabolismo , Animais , Proteínas de Homeodomínio/genética , Imuno-Histoquímica , Interneurônios/metabolismo , Camundongos , Camundongos Mutantes , Interferência de RNA , Proteínas Supressoras de Tumor/genética
16.
Dev Biol ; 301(1): 14-26, 2007 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-17123502

RESUMO

Control over cell cycle exit is fundamental to the normal generation of the wide array of distinct cell types that comprise the mature vertebrate CNS. Here, we demonstrate a critical role for Cip/Kip class cyclin-kinase inhibitory (CKI) proteins in regulating this process during neurogenesis in the embryonic spinal cord. Using immunohistochemistry, we show that all three identified Cip/Kip CKI proteins are expressed in both distinct and overlapping populations of nascent and post-mitotic neurons during early neurogenesis, with p27(Kip1) having the broadest expression, and both p57(Kip2) and p21(Cip1) showing transient expression in restricted populations. Loss- and gain-of-function approaches were used to establish the unique and redundant functions of these proteins in spinal cord neurogenesis. Using genetic lineage tracing, we provide evidence that, in the absence of p57, nascent neurons re-enter the cell cycle inappropriately but later exit to begin differentiation. Analysis of p57(Kip2);p27(Kip1) double mutants, where p21 expression is confined to only a small population of interneurons, demonstrates that Cip/Kip CKI-independent factors initiate progenitor cell cycle exit for the majority of interneurons generated in the developing spinal cord. Our studies indicate that p57 plays a critical cell-autonomous role in timing cell cycle exit at G1/S by opposing the activity of Cyclin D1, which promotes cell cycle progression. These studies support a multi-step model for neuronal progenitor cell cycle withdrawal that involves p57(Kip2) in a central role opposing latent Cyclin D1 and other residual cell cycle promoting activities in progenitors targeted for differentiation.


Assuntos
Ciclo Celular/fisiologia , Diferenciação Celular/efeitos dos fármacos , Proteínas Inibidoras de Quinase Dependente de Ciclina/fisiologia , Neurônios/citologia , Inibidores de Proteínas Quinases/farmacologia , Medula Espinal/efeitos dos fármacos , Animais , Diferenciação Celular/fisiologia , Proteínas Inibidoras de Quinase Dependente de Ciclina/genética , Camundongos , Camundongos Knockout , Mutagênese , Medula Espinal/citologia , Medula Espinal/embriologia
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