We review the molecular basis of several transcription factors (Eya1, Sox2), including the three related genes coding basic helix-loop-helix (bHLH; see abbreviations) proteins (Neurog1, Neurod1, Atoh1) during the development of spiral ganglia, cochlear nuclei, and cochlear hair cells. Neuronal development requires Neurog1, followed by its downstream target Neurod1, to cross-regulate Atoh1 expression. In contrast, hair cells and cochlear nuclei critically depend on Atoh1 and require Neurod1 expression for interactions with Atoh1. Upregulation of Atoh1 following Neurod1 loss changes some vestibular neurons' fate into "hair cells", highlighting the significant interplay between the bHLH genes. Further work showed that replacing Atoh1 by Neurog1 rescues some hair cells from complete absence observed in Atoh1 null mutants, suggesting that bHLH genes can partially replace one another. The inhibition of Atoh1 by Neurod1 is essential for proper neuronal cell fate, and in the absence of Neurod1, Atoh1 is upregulated, resulting in the formation of "intraganglionic" HCs. Additional genes, such as Eya1/Six1, Sox2, Pax2, Gata3, Fgfr2b, Foxg1, and Lmx1a/b, play a role in the auditory system. Finally, both Lmx1a and Lmx1b genes are essential for the cochlear organ of Corti, spiral ganglion neuron, and cochlear nuclei formation. We integrate the mammalian auditory system development to provide comprehensive insights beyond the limited perception driven by singular investigations of cochlear neurons, cochlear hair cells, and cochlear nuclei. A detailed analysis of gene expression is needed to understand better how upstream regulators facilitate gene interactions and mammalian auditory system development.

• MeSH
• Cochlea cytology   metabolism   MeSH
• Humans MeSH
• Neurogenesis genetics   physiology   MeSH
• Basic Helix-Loop-Helix Transcription Factors genetics   metabolism   MeSH
• Transcription Factors genetics   metabolism   MeSH
• Hair Cells, Auditory metabolism   MeSH
• Gene Expression Regulation, Developmental MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Juvenile hormone (JH) signaling is realized at the gene regulatory level by receptors of the bHLH-PAS transcription factor family. The sesquiterpenoid hormones and their synthetic mimics are agonist ligands of a unique JH receptor (JHR) protein, methoprene-tolerant (MET). Upon binding an agonist to its PAS-B cavity, MET dissociates from a cytoplasmic chaperone complex including HSP83 and concomitantly switches to a bHLH-PAS partner taiman, forming a nuclear, transcriptionally active JHR heterodimer. This course of events resembles the vertebrate aryl hydrocarbon receptor (AHR), activated by a plethora of endogenous and synthetic compounds. Like in AHR, the pliable PAS-B cavity of MET adjusts to diverse ligands and binds them through similar mechanisms. Despite recent progress, we only begin to discern agonist-induced conformational shifts within the PAS-B domain, with the ultimate goal of understanding how these localized changes stimulate the assembly of the active JHR complex and, thus, fully grasp the mechanism of JHR signaling.

• MeSH
• Juvenile Hormones * metabolism   MeSH
• Signal Transduction MeSH
• Basic Helix-Loop-Helix Transcription Factors metabolism   genetics   chemistry   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

UNLABELLED: Backround. There is increasing evidence of the role of hypoxia or pseudohypoxia in tumorigenesis, including pheochromocytoma (PHEO) and paraganglioma (PGL). (Pseudo)hypoxia leads to activation of hypoxia-inducible transcription factors (HIFs) and thus, promotes the transcription of hypoxia-responsive genes which are involved in tumorigenesis. Recently identified is a new syndrome consisting of multiple and recurrent PGLs or PHEOs, somatostatinoma, and congenital polycythemia, due to somatic hypoxia-inducible factor 2α gene (HIF2A) mutations. METHODS AND RESULTS: PubMed and Web of Science online databases were used to search reviews and original articles on the HIF, PHEO/PGL, and Pacak-Zhuang syndrome. CONCLUSIONS: The novel somatic and germline gain-of-function HIF2A mutations described latterly emphasize the role of the HIF-2α in the PHEO/PGL development and these findings designate HIF, especially HIF-2α, as a promising treatment target.

• MeSH
• Carcinogenesis genetics   MeSH
• Humans MeSH
• Mutation MeSH
• Paraganglioma drug therapy   genetics   MeSH
• Polycythemia congenital   drug therapy   genetics   MeSH
• Somatostatinoma drug therapy   genetics   MeSH
• Syndrome MeSH
• Basic Helix-Loop-Helix Transcription Factors genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Brassinosteroids (BRs) are essential phytohormones regulating various developmental and physiological processes during normal growth and development.cog1-3D(cogwheel1-3D) was identified as an activation-tagged genetic modifier ofbri1-5, an intermediate BR receptor mutant in Arabidopsis (Arabidopsis thaliana).COG1encodes a Dof-type transcription factor found previously to act as a negative regulator of the phytochrome signaling pathway.cog1-3Dsingle mutants show an elongated hypocotyl phenotype under light conditions. A loss-of-function mutant or inducible expression of a dominant negative form ofCOG1in the wild type results in an opposite phenotype. A BR profile assay indicated that BR levels are elevated incog1-3Dseedlings. Quantitative reverse transcription-polymerase chain reaction analyses showed that several key BR biosynthetic genes are significantly up-regulated incog1-3Dcompared with those of the wild type. Two basic helix-loop-helix transcription factors,PIF4andPIF5, were found to be transcriptionally up-regulated incog1-3DGenetic analysis indicated that PIF4 and PIF5 were required for COG1 to promote BR biosynthesis and hypocotyl elongation. Chromatin immunoprecipitation and electrophoretic mobility shift assays indicated that COG1 binds to the promoter regions ofPIF4andPIF5, and PIF4 and PIF5 bind to the promoter regions of key BR biosynthetic genes, such asDWF4andBR6ox2, to directly promote their expression. These results demonstrated that COG1 regulates BR biosynthesis via up-regulating the transcription ofPIF4andPIF5.

• MeSH
• Arabidopsis genetics   metabolism   MeSH
• Models, Biological MeSH
• Biosynthetic Pathways genetics   MeSH
• Point Mutation genetics   MeSH
• Brassinosteroids biosynthesis   MeSH
• Ethyl Methanesulfonate MeSH
• Phenotype MeSH
• Hypocotyl growth & development   metabolism   MeSH
• Promoter Regions, Genetic genetics   MeSH
• Arabidopsis Proteins genetics   metabolism   MeSH
• Gene Expression Regulation, Plant MeSH
• Genes, Plant MeSH
• Base Sequence MeSH
• Suppression, Genetic MeSH
• Basic Helix-Loop-Helix Transcription Factors genetics   metabolism   MeSH
• Transcription Factors genetics   metabolism   MeSH
• Up-Regulation genetics   MeSH
• Protein Binding genetics   MeSH
• Publication type
• Journal Article MeSH

In the present study, we investigated protein expression of the transcription factors mammalian doublesex and mab-3 related transcription factor 1 (DMRT1), basic helix-loop-helix transcription factor-like 5 (TCLF5), and octamer-binding transcription factor 4 (OCT4) in normal human spermatogenesis, testicular mixed germ cell-sex cord stromal tumor (MGC-SCST), spermatocytic tumor, and seminoma. In normal human spermatogenesis, DMRT1 is expressed in the nuclei of spermatogonia but not in those of more mature germ cells. By way of contrast, TCLF5 is expressed in the nuclei of some clusters of primary spermatocytes that have entered meiosis 1, in secondary spermatocytes, and in round (early) spermatids in the seminiferous tubules of adults during the reproductive years. OCT4 is expressed in primordial germ cells but not in the seminiferous tubules of the normal adult testis during the reproductive years. DMRT1 is expressed in the germ cells of both testicular MGC-SCST and spermatocytic tumor, whereas TCLF5 is not expressed in either neoplasm. These low-grade neoplasms, however, differ histologically in that all the germ cell nuclei of testicular MGC-SCST resemble spermatogonia, whereas in spermatocytic tumor, the nuclei of the medium-sized and large cells resemble those of primary spermatocytes. Both neoplasms lack expression of OCT4. By way of contrast, in seminoma, a fully malignant testicular germ cell tumor, the germ cell nuclei express OCT4 but do not express either DMRT1 or TCLF5.

• MeSH
• Biopsy MeSH
• Cell Nucleus chemistry   pathology   MeSH
• Neoplasms, Germ Cell and Embryonal chemistry   pathology   MeSH
• Immunohistochemistry MeSH
• Humans MeSH
• Biomarkers, Tumor analysis   MeSH
• Octamer Transcription Factor-3 analysis   MeSH
• Seminiferous Tubules chemistry   pathology   MeSH
• Seminoma chemistry   pathology   MeSH
• Spermatocytes chemistry   pathology   MeSH
• Spermatogenesis MeSH
• Testicular Neoplasms chemistry   pathology   MeSH
• Basic Helix-Loop-Helix Transcription Factors analysis   MeSH
• Transcription Factors analysis   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH

Juvenile hormones (JHs) play a major role in controlling development and reproduction in insects and other arthropods. Synthetic JH-mimicking compounds such as methoprene are employed as potent insecticides against significant agricultural, household and disease vector pests. However, a receptor mediating effects of JH and its insecticidal mimics has long been the subject of controversy. The bHLH-PAS protein Methoprene-tolerant (Met), along with its Drosophila melanogaster paralog germ cell-expressed (Gce), has emerged as a prime JH receptor candidate, but critical evidence that this protein must bind JH to fulfill its role in normal insect development has been missing. Here, we show that Gce binds a native D. melanogaster JH, its precursor methyl farnesoate, and some synthetic JH mimics. Conditional on this ligand binding, Gce mediates JH-dependent gene expression and the hormone's vital role during development of the fly. Any one of three different single amino acid mutations in the ligand-binding pocket that prevent binding of JH to the protein block these functions. Only transgenic Gce capable of binding JH can restore sensitivity to JH mimics in D. melanogaster Met-null mutants and rescue viability in flies lacking both Gce and Met that would otherwise die at pupation. Similarly, the absence of Gce and Met can be compensated by expression of wild-type but not mutated transgenic D. melanogaster Met protein. This genetic evidence definitively establishes Gce/Met in a JH receptor role, thus resolving a long-standing question in arthropod biology.

• MeSH
• Cell Line MeSH
• Drosophila melanogaster embryology   genetics   MeSH
• Animals, Genetically Modified MeSH
• Juvenile Hormones metabolism   MeSH
• Fatty Acids, Unsaturated metabolism   MeSH
• Drosophila Proteins genetics   MeSH
• Signal Transduction genetics   MeSH
• Basic Helix-Loop-Helix Transcription Factors genetics   MeSH
• Transcription Factors genetics   MeSH
• Protein Binding physiology   MeSH
• Gene Expression Regulation, Developmental genetics   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

The tissue distribution and prognostic relevance of subtype-specific proteins (ASCL1, NEUROD1, POU2F3, YAP1) present an evolving area of research in small-cell lung cancer (SCLC). The expression of subtype-specific transcription factors and P53 and RB1 proteins were measured by immunohistochemistry (IHC) in 386 surgically resected SCLC samples. Correlations between subtype-specific proteins and in vitro efficacy of various therapeutic agents were investigated by proteomics and cell viability assays in 26 human SCLC cell lines. Besides SCLC-A (ASCL1-dominant), SCLC-AN (combined ASCL1/NEUROD1), SCLC-N (NEUROD1-dominant), and SCLC-P (POU2F3-dominant), IHC and cluster analyses identified a quadruple-negative SCLC subtype (SCLC-QN). No unique YAP1-subtype was found. The highest overall survival rates were associated with non-neuroendocrine subtypes (SCLC-P and SCLC-QN) and the lowest with neuroendocrine subtypes (SCLC-A, SCLC-N, SCLC-AN). In univariate analyses, high ASCL1 expression was associated with poor prognosis and high POU2F3 expression with good prognosis. Notably, high ASCL1 expression influenced survival outcomes independently of other variables in a multivariate model. High POU2F3 and YAP1 protein abundances correlated with sensitivity and resistance to standard-of-care chemotherapeutics, respectively. Specific correlation patterns were also found between the efficacy of targeted agents and subtype-specific protein abundances. In conclusion, we investigated the clinicopathological relevance of SCLC molecular subtypes in a large cohort of surgically resected specimens. Differential IHC expression of ASCL1, NEUROD1, and POU2F3 defines SCLC subtypes. No YAP1-subtype can be distinguished by IHC. High POU2F3 expression is associated with improved survival in a univariate analysis, whereas elevated ASCL1 expression is an independent negative prognosticator. Proteomic and cell viability assays of human SCLC cell lines revealed distinct vulnerability profiles defined by transcription regulators. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

• MeSH
• Humans MeSH
• Small Cell Lung Carcinoma * genetics   metabolism   surgery   MeSH
• Cell Line, Tumor MeSH
• Lung Neoplasms * genetics   metabolism   surgery   MeSH
• Prognosis MeSH
• Proteomics MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Basic Helix-Loop-Helix Transcription Factors genetics   metabolism   MeSH
• Transcription Factors genetics   metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH

• MeSH
• Humans MeSH
• Mutation MeSH
• Duodenal Neoplasms genetics   metabolism   pathology   MeSH
• Paraganglioma genetics   metabolism   pathology   MeSH
• Basic Helix-Loop-Helix Transcription Factors genetics   metabolism   MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Letter MeSH
• Research Support, N.I.H., Intramural MeSH

Reprogramming of non-endocrine pancreatic cells into insulin-producing cells represents a promising therapeutic approach for the restoration of endogenous insulin production in diabetic patients. In this paper, we report that human organoid cells derived from the pancreatic tissue can be reprogrammed into the insulin-producing cells (IPCs) by the combination of in vitro transcribed modified mRNA encoding transcription factor neurogenin 3 and small molecules modulating the epigenetic state and signalling pathways. Upon the reprogramming, IPCs formed 4.6 ± 1.2 % of the total cells and expressed typical markers (insulin, glucokinase, ABCC8, KCNJ11, SLC2A2, SLC30A8) and transcription factors (PDX1, NEUROD1, MAFA, NKX2.2, NKX6.1, PAX4, PAX6) needed for the proper function of pancreatic β-cells. Additionally, we have revealed a positive effect of ALK5 inhibitor RepSox on the overall reprogramming efficiency. However, the reprogrammed IPCs possessed only a partial insulin-secretory capacity, as they were not able to respond to the changes in the extracellular glucose concentration by increasing insulin secretion. Based on the achieved results we conclude that due to the incomplete reprogramming, the IPCs have immature character and only partial properties of native human β-cells.

• MeSH
• AC133 Antigen metabolism   MeSH
• Insulin-Secreting Cells cytology   drug effects   MeSH
• Adult MeSH
• Transcription, Genetic drug effects   MeSH
• Insulin biosynthesis   MeSH
• Small Molecule Libraries pharmacology   MeSH
• Humans MeSH
• RNA, Messenger genetics   metabolism   MeSH
• Organoids cytology   MeSH
• Cellular Reprogramming drug effects   genetics   MeSH
• Cell Proliferation MeSH
• Nerve Tissue Proteins genetics   metabolism   MeSH
• Basic Helix-Loop-Helix Transcription Factors genetics   metabolism   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

The sesquiterpenoid juvenile hormone (JH) is vital to insect development and reproduction. Intracellular JH receptors have recently been established as basic helix-loop-helix transcription factor (bHLH)/PAS proteins in Drosophila melanogaster known as germ cell-expressed (Gce) and its duplicate paralog, methoprene-tolerant (Met). Upon binding JH, Gce/Met activates its target genes. Insects possess multiple native JH homologs whose molecular activities remain unexplored, and diverse synthetic compounds including insecticides exert JH-like effects. How the JH receptor recognizes its ligands is unknown. To determine which structural features define an active JH receptor agonist, we tested several native JHs and their nonnative geometric and optical isomers for the ability to bind the Drosophila JH receptor Gce, to induce Gce-dependent transcription, and to affect the development of the fly. Our results revealed high ligand stereoselectivity of the receptor. The geometry of the JH skeleton, dictated by two stereogenic double bonds, was the most critical feature followed by the presence of an epoxide moiety at a terminal position. The optical isomerism at carbon C11 proved less important even though Gce preferentially bound a natural JH enantiomer. The results of receptor-ligand-binding and cell-based gene activation assays tightly correlated with the ability of different geometric JH isomers to induce gene expression and morphogenetic effects in the developing insects. Molecular modeling supported the requirement for the proper double-bond geometry of JH, which appears to be its major selective mechanism. The strict stereoselectivity of Gce toward the natural hormone contrasts with the high potency of synthetic Gce agonists of disparate chemistries.

• MeSH
• Drosophila melanogaster chemistry   genetics   metabolism   MeSH
• Juvenile Hormones chemistry   metabolism   MeSH
• Models, Molecular MeSH
• Drosophila Proteins metabolism   MeSH
• Receptors, Cell Surface metabolism   MeSH
• Stereoisomerism MeSH
• Basic Helix-Loop-Helix Transcription Factors metabolism   MeSH
• Transcription Factors metabolism   MeSH
• Protein Binding MeSH
• Gene Expression Regulation, Developmental MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH