scholarly journals ALK4 coordinates extracellular and intrinsic signals to regulate development of cortical somatostatin interneurons

2019 ◽  
Vol 219 (1) ◽  
Author(s):  
Christina Göngrich ◽  
Favio A. Krapacher ◽  
Hermany Munguba ◽  
Diana Fernández-Suárez ◽  
Annika Andersson ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Gene Promoter ◽  
Double Positive ◽  
Intrinsic Signals ◽  
Cortical Interneuron ◽  
Extracellular Signals ◽  
Inhibitory Circuitry ◽  
Cortical Interneurons ◽  
Interneuron Development

Although the role of transcription factors in fate specification of cortical interneurons is well established, how these interact with extracellular signals to regulate interneuron development is poorly understood. Here we show that the activin receptor ALK4 is a key regulator of the specification of somatostatin interneurons. Mice lacking ALK4 in GABAergic neurons of the medial ganglionic eminence (MGE) showed marked deficits in distinct subpopulations of somatostatin interneurons from early postnatal stages of cortical development. Specific losses were observed among distinct subtypes of somatostatin+/Reelin+ double-positive cells, including Hpse+ layer IV cells targeting parvalbumin+ interneurons, leading to quantitative alterations in the inhibitory circuitry of this layer. Activin-mediated ALK4 signaling in MGE cells induced interaction of Smad2 with SATB1, a transcription factor critical for somatostatin interneuron development, and promoted SATB1 nuclear translocation and repositioning within the somatostatin gene promoter. These results indicate that intrinsic transcriptional programs interact with extracellular signals present in the environment of MGE cells to regulate cortical interneuron specification.

scholarly journals Activin receptor ALK4 coordinates extracellular signals and intrinsic transcriptional programs to regulate development of cortical somatostatin interneurons

2019 ◽  
Author(s):  
Christina Göngrich ◽  
Favio A. Krapacher ◽  
Hermany Munguba ◽  
Diana Fernández-Suárez ◽  
Annika Andersson ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Gene Promoter ◽  
Double Positive ◽  
Activin Receptor ◽  
Cortical Interneuron ◽  
Extracellular Signals ◽  
Inhibitory Circuitry ◽  
Cortical Interneurons ◽  
Interneuron Development

AbstractAlthough the role of transcription factors in fate specification of cortical interneurons is well established, how these interact with extracellular signals to regulate interneuron development is poorly understood. Here we show that the activin receptor ALK4 is a key regulator of the specification of somatostatin interneurons. Mice lacking ALK4 in GABAergic neurons of the medial ganglionic eminence (MGE) showed marked deficits in distinct subpopulations of somatostatin interneurons from early postnatal stages of cortical development. Specific loses were observed among distinct subtypes of somatostatin+/Reelin+ double-positive cells, including Hpse+ layer IV cells targeting parvalbumin+ interneurons, leading to quantitative alterations in the inhibitory circuitry of this layer. Activin-mediated ALK4 signaling in MGE cells induced interaction of Smad2 with SATB1, a transcription factor critical for somatostatin interneuron development, and promoted SATB1 nuclear translocation and repositioning within the somatostatin gene promoter. These results indicate that intrinsic transcriptional programs interact with extracellular signals present in the environment of MGE cells to regulate cortical interneuron specification.

scholarly journals Nuclear ErbB2 represses DEPTOR transcription to inhibit autophagy in breast cancer cells

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Yanli Bi ◽  
Longyuan Gong ◽  
Pengyuan Liu ◽  
Xiufang Xiong ◽  
Yongchao Zhao
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Transcriptional Repression ◽  
Breast Cancer Cells ◽  
Kinase Activity ◽  
Nuclear Translocation ◽  
Extracellular Signals ◽  
Consensus Binding Sequence ◽  
Binding Sequence

AbstractErbB2, a classical receptor tyrosine kinase, is frequently overexpressed in breast cancer cells. Although the role of ErbB2 in the transmission of extracellular signals to intracellular matrix has been widely studied, the functions of nuclear ErbB2 remain largely elusive. Here, we report a novel function of nuclear ErbB2 in repressing the transcription of DEPTOR, a direct inhibitor of mTOR. Nuclear ErbB2 directly binds to the consensus binding sequence in the DEPTOR promoter to repress its transcription. The kinase activity of ErbB2 is required for its nuclear translocation and transcriptional repression of DEPTOR. Moreover, the repressed DEPTOR by nuclear ErbB2 inhibits the induction of autophagy by activating mTORC1. Thus, our study reveals a novel mechanism for autophagy regulation by functional ErbB2, which translocates to the nucleus and acts as a transcriptional regulator to suppress DEPTOR transcription, leading to activation of the PI3K/AKT/mTOR pathway to inhibit autophagy.

scholarly journals Foxg1 Regulates the Postnatal Development of Cortical Interneurons

2018 ◽  
Vol 29 (4) ◽  
pp. 1547-1560 ◽  
Author(s):  
Wei Shen ◽  
Ru Ba ◽  
Yan Su ◽  
Yang Ni ◽  
Dongsheng Chen ◽  
...  
Keyword(s):  
Postnatal Development ◽  
Neural Circuit ◽  
Neurological Diseases ◽  
Cortical Interneuron ◽  
Conditional Deletion ◽  
Cortical Interneurons ◽  
Migration Capacity ◽  
Dendritic Complexity ◽  
Foxg1 Syndrome

AbstractAbnormalities in cortical interneurons are closely associated with neurological diseases. Most patients with Foxg1 syndrome experience seizures, suggesting a possible role of Foxg1 in the cortical interneuron development. Here, by conditional deletion of Foxg1, which was achieved by crossing Foxg1fl/fl with the Gad2-CreER line, we found the postnatal distributions of somatostatin-, calretinin-, and neuropeptide Y-positive interneurons in the cortex were impaired. Further investigations revealed an enhanced dendritic complexity and decreased migration capacity of Foxg1-deficient interneurons, accompanied by remarkable downregulation of Dlx1 and CXCR4. Overexpression of Dlx1 or knock down its downstream Pak3 rescued the differentiation detects, demonstrated that Foxg1 functioned upstream of Dlx1-Pak3 signal pathway to regulate the postnatal development of cortical interneurons. Due to the imbalanced neural circuit, Foxg1 mutants showed increased seizure susceptibility. These findings will improve our understanding of the postnatal development of interneurons and help to elucidate the mechanisms underlying seizure in patients carrying Foxg1 mutations.

scholarly journals The Role of Nuclear Insulin and IGF1 Receptors in Metabolism and Cancer

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 531
Author(s):  
Haim Werner ◽  
Rive Sarfstein ◽  
Zvi Laron
Keyword(s):  
Transcriptional Control ◽  
Nuclear Translocation ◽  
Biological Activities ◽  
Gene Promoter ◽  
Physiological Relevance ◽  
Typical Cell ◽  
Cognate Gene ◽  
Surface Localization ◽  
Definition Of

Insulin (InsR) and insulin-like growth factor-1 (IGF1R) receptors mediate the metabolic and growth-promoting actions of insulin and IGF1/IGF2, respectively. Evidence accumulated in recent years indicates that, in addition to their typical cell-surface localization pattern and ligand-activated mechanism of action, InsR and IGF1R are present in the cell nucleus of both normal and transformed cells. Nuclear translocation seems to involve interaction with a small, ubiquitin-like modifier protein (SUMO-1), although this modification is not always a prerequisite. Nuclear InsR and IGF1R exhibit a number of biological activities that classically fit within the definition of transcription factors. These nuclear activities include, among others, sequence-specific DNA binding and transcriptional control. Of particular interest, nuclear IGF1R was capable of binding and stimulating its cognate gene promoter. The physiological relevance of this autoregulatory mechanism needs to be further investigated. In addition to its nuclear localization, studies have identified IGF1R in the Golgi apparatus, and this particular distribution correlated with a migratory phenotype. In summary, the newly described roles of InsR and IGF1R as gene regulators, in concert with their atypical pattern of subcellular distribution, add a further layer of complexity to traditional models of cell signaling. Furthermore, and in view of the emerging role of IGF1R as a potential therapeutic target, a better understanding of the mechanisms responsible for nuclear IGF1R transport and identification of IGF1R interactors might help optimize target directed therapies in oncology.

scholarly journals N-cadherin (Cdh2) Maintains Migration and Postmitotic Survival of Cortical Interneuron Precursors in a Cell-Type-Specific Manner

2019 ◽  
Vol 30 (3) ◽  
pp. 1318-1329
Author(s):  
Zsófia I László ◽  
Kinga Bercsényi ◽  
Mátyás Mayer ◽  
Kornél Lefkovics ◽  
Gábor Szabó ◽  
...  
Keyword(s):  
Target Selection ◽  
Cortical Plate ◽  
Specific Factor ◽  
Cell Type ◽  
Cortical Interneuron ◽  
Specific Manner ◽  
A Cell ◽  
Cell Type Specific ◽  
Interneuron Development

Abstract The multiplex role of cadherin-based adhesion complexes during development of pallial excitatory neurons has been thoroughly characterized. In contrast, much less is known about their function during interneuron development. Here, we report that conditional removal of N-cadherin (Cdh2) from postmitotic neuroblasts of the subpallium results in a decreased number of Gad65-GFP-positive interneurons in the adult cortex. We also found that interneuron precursor migration into the pallium was already delayed at E14. Using immunohistochemistry and TUNEL assay in the embryonic subpallium, we excluded decreased mitosis and elevated cell death as possible sources of this defect. Moreover, by analyzing the interneuron composition of the adult somatosensory cortex, we uncovered an unexpected interneuron-type-specific defect caused by Cdh2-loss. This was not due to a fate-switch between interneuron populations or altered target selection during migration. Instead, potentially due to the migration delay, part of the precursors failed to enter the cortical plate and consequently got eliminated at early postnatal stages. In summary, our results indicate that Cdh2-mediated interactions are necessary for migration and survival during the postmitotic phase of interneuron development. Furthermore, we also propose that unlike in pallial glutamatergic cells, Cdh2 is not universal, rather a cell type-specific factor during this process.

scholarly journals JAK-STAT in Early Hematopoiesis and Leukemia

2021 ◽  
Vol 9 ◽  
Author(s):  
Eirini Sofia Fasouli ◽  
Eleni Katsantoni
Keyword(s):  
Hematologic Malignancies ◽  
Janus Kinase ◽  
Hematopoietic Stem ◽  
Intrinsic Signals ◽  
Extracellular Signals ◽  
Bm Niche ◽  
Pathway Activation ◽  
Research Findings ◽  
Stat Pathway

Hematopoietic stem cells (HSCs) produce all the terminally differentiated blood cells and are controlled by extracellular signals from the microenvironment, the bone marrow (BM) niche, as well as intrinsic cell signals. Intrinsic signals include the tightly controlled action of signaling pathways, as the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. Activation of JAK-STAT leads to phosphorylation of members of the STAT family to regulate proliferation, survival, and self-renewal of HSCs. Mutations in components of the JAK-STAT pathway are linked with defects in HSCs and hematologic malignancies. Accumulating mutations in HSCs and aging contribute to leukemia transformation. Here an overview of hematopoiesis, and the role of the JAK-STAT pathway in HSCs and in the promotion of leukemic transformation is presented. Therapeutic targeting of JAK-STAT and clinical implications of the existing research findings are also discussed.

The Role of TNFalpha Gene Promoter Polymorphism in the Development of Coal Workers' Pneumoconiosis

2002 ◽  
Vol 14 (2) ◽  
pp. 117
Author(s):  
Byoung Yong Ahn ◽  
Kyoung Ah Kim ◽  
Hae Yun Nam ◽  
Je Hyeok Mun ◽  
Jin Sook Jeoung ◽  
...  
Keyword(s):  
Gene Promoter ◽  
Promoter Polymorphism ◽  
Coal Workers Pneumoconiosis ◽  
Coal Workers ◽  
Gene Promoter Polymorphism

scholarly journals EGFR-ERK induced activation of GRHL1 promotes cell cycle progression by up-regulating cell cycle related genes in lung cancer

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Yiming He ◽  
Mingxi Gan ◽  
Yanan Wang ◽  
Tong Huang ◽  
Jianbin Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Potential Role ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Phosphorylation Site ◽  
Promoter Regions ◽  
Cycle Progression

AbstractGrainyhead-like 1 (GRHL1) is a transcription factor involved in embryonic development. However, little is known about the biological functions of GRHL1 in cancer. In this study, we found that GRHL1 was upregulated in non-small cell lung cancer (NSCLC) and correlated with poor survival of patients. GRHL1 overexpression promoted the proliferation of NSCLC cells and knocking down GRHL1 inhibited the proliferation. RNA sequencing showed that a series of cell cycle-related genes were altered when knocking down GRHL1. We further demonstrated that GRHL1 could regulate the expression of cell cycle-related genes by binding to the promoter regions and increasing the transcription of the target genes. Besides, we also found that EGF stimulation could activate GRHL1 and promoted its nuclear translocation. We identified the key phosphorylation site at Ser76 on GRHL1 that is regulated by the EGFR-ERK axis. Taken together, these findings elucidate a new function of GRHL1 on regulating the cell cycle progression and point out the potential role of GRHL1 as a drug target in NSCLC.

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