Role of myofiber-specific FoxP1 in pancreatic cancer-induced muscle wasting.

Cancer cachexia affects up to 80% of patients with cancer and results in reduced quality of life and survival. We previously demonstrated that the transcriptional repressor Forkhead box P1 (FoxP1) is upregulated in the skeletal muscle of cachectic mice and people with cancer, and when overexpressed in skeletal muscle, it is sufficient to induce pathological features characteristic of cachexia. However, the role of myofiber-derived FoxP1 in both normal muscle physiology and cancer-induced muscle wasting remains largely unexplored.

Myofiber-specific FoxP1 knockout protects against pancreatic cancer-induced muscle wasting in male but not female mice.

Cancer cachexia affects up to 80% of cancer patients and results in reduced quality of life and survival. We previously demonstrated that the transcriptional repressor Forkhead box P1 (FoxP1) is upregulated in skeletal muscle of cachectic mice and people with cancer, and when overexpressed in skeletal muscle is sufficient to induce pathological features characteristic of cachexia. However, the role of myofiber-derived FoxP1 in both normal muscle physiology and cancer-induced muscle wasting remains largely unexplored.

Lymphoid origin of intrinsically activated plasmacytoid dendritic cells in mice.

We identified a novel mouse plasmacytoid dendritic cell (pDC) lineage derived from the common lymphoid progenitors (CLPs) that is dependent on expression of . These CLP-derived pDCs, which we refer to as 'B-pDCs', have a unique gene expression profile that includes hallmark B cell genes, normally not expressed in conventional pDCs. Despite expressing most classical pDC markers such as SIGLEC-H and PDCA1, B-pDCs lack IFN-α secretion, exhibiting a distinct inflammatory profile.

Polyethylene glycol has immunoprotective effects on sciatic allografts, but behavioral recovery and graft tolerance require neurorrhaphy and axonal fusion.

JOURNAL/nrgr/04.03/01300535-202504000-00033/figure1/v/2024-07-06T104127Z/r/image-tiff Behavioral recovery using (viable) peripheral nerve allografts to repair ablation-type (segmental-loss) peripheral nerve injuries is delayed or poor due to slow and inaccurate axonal regeneration. Furthermore, such peripheral nerve allografts undergo immunological rejection by the host immune system.

The malignant transformation potential of the oncogene STYK1/NOK at early lymphocyte development in transgenic mice.

B-cell Chronic Lymphocytic Leukemia (B-CLL) is a malignancy caused by the clonal expansion of mature B lymphocytes bearing a CD5CD19 (B1) phenotype. However, the origin of B-CLL remains controversial. We showed previously that STYK1/NOK transgenic mice develop a CLL-like disease.

Established and Evolving Roles of the Multifunctional Non-POU Domain-Containing Octamer-Binding Protein (NonO) and Splicing Factor Proline- and Glutamine-Rich (SFPQ).

It has been more than three decades since the discovery of multifunctional factors, the Non-POU-Domain-Containing Octamer-Binding Protein, NonO, and the Splicing Factor Proline- and Glutamine-Rich, SFPQ. Some of their functions, including their participation in transcriptional and posttranscriptional regulation as well as their contribution to paraspeckle subnuclear body organization, have been well documented. In this review, we focus on several other established roles of NonO and SFPQ, including their participation in the cell cycle, nonhomologous end-joining (NHEJ), homologous recombination (HR), telomere stability, childhood birth defects and cancer.

Deacetylation of FOXP1 by HDAC7 potentiates self-renewal of mesenchymal stem cells.

Background: Mesenchymal stem cells (MSCs) are widely used in a variety of tissue regeneration and clinical trials due to their multiple differentiation potency. However, it remains challenging to maintain their replicative capability during in vitro passaging while preventing their premature cellular senescence. Forkhead Box P1 (FOXP1), a FOX family transcription factor, has been revealed to regulate MSC cell fate commitment and self-renewal capacity in our previous study.

Lysine Methyltransferase SMYD1 Regulates Myogenesis via skNAC Methylation.

The SMYD family is a unique class of lysine methyltransferases (KMTases) whose catalytic SET domain is split by a MYND domain. Among these, Smyd1 was identified as a heart- and skeletal muscle-specific KMTase and is essential for cardiogenesis and skeletal muscle development. SMYD1 has been characterized as a histone methyltransferase (HMTase).

Induction of chronic lymphocytic leukemia-like disease in STYK1/NOK transgenic mice.

STYK1/NOK functions in a ligand independent and constitutive fashion to provoke tumor formation and to be up-regulated in many types of cancer cells. However, how STYK1/NOK functions at the whole animal level is completely unknown. Here, we found that STYK1/NOK-transgenic (tg) mice spontaneously developed immunosuppressive B-CLL-like disease with generally shorter life spans.

Anticancer potential of nitric oxide (NO) in neuroblastoma treatment.

The most common extracranial solid tumor in childhood, paediatric neuroblastoma, is frequently diagnosed at advanced stages and identified as high risk. High risk neuroblastoma is aggressive and unpredictable, resulting in poor prognosis and only ∼40% five-year survival rates. Herein, nitric oxide (NO) delivered the -nitrosothiol, -nitrosoglutathione (GSNO), is explored as an anticancer therapeutic in various neuroblastoma lines.

The SMYD1 and skNAC transcription factors contribute to neurodegenerative diseases.

SMYD1 and the skNAC isoform of the NAC transcription factor have both previously been characterized as transcription factors in hematopoiesis and cardiac/skeletal muscle. Here we report that comparative analysis of genes deregulated by SMYD1 or skNAC knockdown in differentiating C2C12 myoblasts identified transcripts characteristic of neurodegenerative diseases, including Alzheimer's, Parkinson's and Huntington's Diseases (AD, PD, and HD). This led us to determine whether SMYD1 and skNAC function together or independently within the brain.

Forkhead box P1 (Foxp1) in osteoblasts regulates bone mass accrual and adipose tissue energy metabolism.

Adiponectin (AdipoQ), a hormone abundantly secreted by adipose tissues, has multiple beneficial functions, including insulin sensitization as well as lipid and glucose metabolism. It has been reported that bone controls energy metabolism through an endocrine-based mechanism. In this study, we observed that bone also acts as an important endocrine source for AdipoQ, and its capacity in osteoblasts is controlled by the forkhead box P1 (FOXP1) transcriptional factor.

Lipid Rafts Interaction of the ARID3A Transcription Factor with EZRIN and G-Actin Regulates B-Cell Receptor Signaling.

Several diseases originate via dysregulation of the actin cytoskeleton. The ARID3A/Bright transcription factor has also been implicated in malignancies, primarily those derived from hematopoietic lineages. Previously, we demonstrated that ARID3A shuttles between the nucleus and the plasma membrane, where it localizes within lipid rafts.

FOXP1 Interacts with MyoD to Repress its Transcription and Myoblast Conversion.

Forkhead transcription factors (TFs) often dimerize outside their extensive family, whereas bHLH transcription factors typically dimerize with E12/E47. Based on structural similarities, we predicted that a member of the former, Forkhead Box P1 (FOXP1), might heterodimerize with a member of the latter, MYOD1 (MyoD). Data shown here support this hypothesis and further demonstrate the specificity of this forkhead/myogenic interaction among other myogenic regulatory factors.

Coding transcriptome analyses reveal altered functions underlying immunotolerance of PEG-fused rat sciatic nerve allografts.

Background: Current methods to repair ablation-type peripheral nerve injuries (PNIs) using peripheral nerve allografts (PNAs) often result in poor functional recovery due to immunological rejection as well as to slow and inaccurate outgrowth of regenerating axonal sprouts. In contrast, ablation-type PNIs repaired by PNAs, using a multistep protocol in which one step employs the membrane fusogen polyethylene glycol (PEG), permanently restore sciatic-mediated behaviors within weeks. Axons and cells within PEG-fused PNAs remain viable, even though outbred host and donor tissues are neither immunosuppressed nor tissue matched.

Polyethylene glycol-fusion repair of sciatic allografts in female rats achieves immunotolerance via attenuated innate and adaptive responses.

Ablation/segmental loss peripheral nerve injuries (PNIs) exhibit poor functional recovery due to slow and inaccurate outgrowth of regenerating axons. Viable peripheral nerve allografts (PNAs) as growth-guide conduits are immunologically rejected and all anucleated donor/host axonal segments undergo Wallerian degeneration. In contrast, we report that ablation-type sciatic PNIs repaired by neurorrhaphy of viable sciatic PNAs and a polyethylene glycol (PEG)-fusion protocol using PEG immediately restored axonal continuity for many axons, reinnervated/maintained their neuromuscular junctions, and prevented much Wallerian degeneration.

Formulation strategies in immunotherapeutic pharmaceutical products.

Development of immunologic-based biopharmaceutical products have strikingly increased in recent years and have made evident contributions to human health. Antibodies are the leading entity in immunotherapy, while chimeric antigen receptor T cells therapies are the advent of a novel strategy in this area. In order to enable antibody candidates or cells available as products, formulation is critical in terms of stabilize molecules or cells to achieve practical shelf life, storage and handling conditions.

The Lysine Methyltransferase SMYD2 Is Required for Definite Hematopoietic Stem Cell Production in the Mouse Embryo.

The five-membered SET and MYND domain-containing lysine methyltransferase (SMYD) family plays pivotal roles in development and differentiation. Initially characterized within the cardiovascular system, one such member, SMYD2, has been implicated in transcriptional and apoptotic regulation of hematopoiesis. Deletion of in adult mouse Hemaopoietic Stem Cells (HSC) using an interferon-inducible -Cre-mediated conditional knockout (CKO) led to HSC reduction via both apoptosis and transcriptional deficiencies.

The lysine methyltransferase SMYD2 is required for normal lymphocyte development and survival of hematopoietic leukemias.

The five membered SET and MYND Domain-containing lysine methyltransferase (SMYD) family plays pivotal roles in development and proliferation. Initially characterized within the cardiovascular system, one such member, SMYD2, has been implicated as an oncogene in leukemias deriving from flawed hematopoietic stem cell (HSC) differentiation. We show here that conditional SMYD2 loss disrupts hematopoiesis at and downstream of the HSC via both apoptotic loss and transcriptional deregulation of HSC proliferation and disruption of Wnt-β-Catenin signaling.

Foxp1 Regulates Neural Stem Cell Self-Renewal and Bias Toward Deep Layer Cortical Fates.

The laminar architecture of the mammalian neocortex depends on the orderly generation of distinct neuronal subtypes by apical radial glia (aRG) during embryogenesis. Here, we identify critical roles for the autism risk gene Foxp1 in maintaining aRG identity and gating the temporal competency for deep-layer neurogenesis. Early in development, aRG express high levels of Foxp1 mRNA and protein, which promote self-renewing cell divisions and deep-layer neuron production.

Foxp1 controls brown/beige adipocyte differentiation and thermogenesis through regulating β3-AR desensitization.

β-Adrenergic receptor (β-AR) signaling is a pathway controlling adaptive thermogenesis in brown or beige adipocytes. Here we investigate the biological roles of the transcription factor Foxp1 in brown/beige adipocyte differentiation and thermogenesis. Adipose-specific deletion of Foxp1 leads to an increase of brown adipose activity and browning program of white adipose tissues.

Loss of the FOXP1 Transcription Factor Leads to Deregulation of B Lymphocyte Development and Function at Multiple Stages.

The FOXP1 transcription factor is expressed throughout B cell development until its extinction just prior to terminal differentiation. nulls die of cardiac defects at midgestation, but adult rescue via fetal liver transfer led to a strong pre-B cell block. To circumvent these limitations and to investigate FOXP1 function at later stages of B cell differentiation, we generated and analyzed floxed (F) alleles deleted at pro-B, transitional (T) 1, and mature B cell stages.

Influence of Commensal Microbiota in Barrier Function of Intestinal Mucosal Epithelium.

This review discusses the current state of knowledge surrounding the role of commensal bacteria in supporting intestinal mucosal barrier protection. We focus on two aspects of physical barrier function: Tight junction maintenance and mucus production.

Loss of SMYD1 Results in Perinatal Lethality via Selective Defects within Myotonic Muscle Descendants.

SET and MYND Domain 1 (SMYD1) is a cardiac and skeletal muscle-specific, histone methyl transferase that is critical for both embryonic and adult heart development and function in both mice and men. We report here that skeletal muscle-specific, -mediated conditional knockout (CKO) of results in perinatal death. As early as embryonic day 12.

Foxp1 Is Indispensable for Ductal Morphogenesis and Controls the Exit of Mammary Stem Cells from Quiescence.

Long-lived quiescent mammary stem cells (MaSCs) are presumed to coordinate the dramatic expansion of ductal epithelium that occurs through the different phases of postnatal development, but little is known about the molecular regulators that underpin their activation. We show that ablation of the transcription factor Foxp1 in the mammary gland profoundly impairs ductal morphogenesis, resulting in a rudimentary tree throughout life. Foxp1-deficient glands were highly enriched for quiescent Tspan8 MaSCs, which failed to become activated even in competitive transplantation assays, thus highlighting a cell-intrinsic defect.