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Results for “Basic helix-loop-helix (bHLH)”

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PubMed2003

Induction of neurogenin-1 expression by sonic hedgehog: Its role in development of trigeminal sensory neurons.

We have examined the roles of signaling molecules in the mechanisms underlying the induction of neurogenin (ngn)-1 expression. ngn-1 is a basic helix-loop-helix (bHLH) transcription factor, which is essential for the specification of trigeminal sensory neurons. Semiquantitative reverse transcriptase-polymerase chain reaction using cranial explants in organ cultures showed that sonic hedgehog (Shh) promotes ngn-1 expression. This promoting activity was not observed in other signaling molecules examined. The promotion of ngn-1 expression by Shh, furthermore, was inhibited by cyclopamine, a specific inhibitor of Shh signaling. Shh did not affect the expression of ngn-2, a bHLH transcription factor that plays an important role in the specification of epibranchial placode-derived sensory neurons. The expression levels of ngn-1 and ngn-2 decreased after fibroblast growth factor-2 treatment. These results suggest that Shh induces ngn-1 expression specifically and that expression of ngn-1 and ngn-2 is regulated by different mechanisms. The induction of ngn-1 expression by Shh suggests that this signaling molecule participates in the specification of trigeminal sensory neurons. We therefore examined the effect of Shh on the development of these neurons. Immunostaining using anti-ngn-1 demonstrated that Shh promotes ngn-1 expression in trigeminal neural crest cells. Trigeminal neural crest cells are derived from the posterior mesencephalon and the most-anterior rhombencephalon, and they contain a subset of precursors of trigeminal sensory neurons. Moreover, a subpopulation of trigeminal neural crest cells expressed the Shh receptor Patched. The number of cells that express Brn3a, a POU-domain transcription factor that plays an important role in differentiation of sensory neurons, also increased with Shh treatment. Our data suggest that Shh signaling is involved in the specification of trigeminal sensory neurons through the induction of ngn-1 expression. Furthermore, Shh promotes the differentiation of neural crest cells into trigeminal sensory neurons.

Animals↗

PubMed2003

Identification of BOIP, a novel cDNA highly expressed during spermatogenesis that encodes a protein interacting with the orange domain of the hairy-related transcription factor HRT1/Hey1 in Xenopus and mouse.

Hairy-related transcription factor (HRT/Hey) genes encode a novel subfamily of basic helix-loop-helix (bHLH) transcription factors related to the Drosophila hairy and Enhancer-of-split (E(spl)) and the mammalian HES proteins that function as downstream mediators of Notch signaling. Using the yeast two-hybrid approach, a previously uncharacterized protein was identified in Xenopus that interacts with XHRT1 (originally referred to as bc8), one member of the HRT/Hey subclass. This protein is evolutionarily conserved in chordates. It binds to sequences adjacent to the bHLH domain of XHRT1 known as the Orange domain and has been named bc8 Orange interacting protein (BOIP). BOIP shows a rather uniform subcellular localization and is recruited to the nucleus upon binding to XHRT1. In Xenopus, XBOIP mRNA is detected by RNase protection analysis throughout embryogenesis. In the adult, the strongest expression is detected in testis. In the mouse, high levels of BOIP mRNA are also found in adult testis. No expression is detected in the embryo and in any of the other adult organs tested. In situ hybridization revealed that BOIP transcripts were detected almost exclusively in round spermatids and that this expression overlaps with that of Hey1 (HRT1), which is expressed throughout spermatogenesis. In view of the importance of the Orange domain for HRT/Hey function, the newly identified BOIP proteins may serve as regulators specifically of HRT1/Hey1 activity.

Amino Acid Sequence↗

PubMed2001

Two upstream enhancers collaborate to regulate the spatial patterning and timing of MyoD transcription during mouse development.

MyoD is a member of the basic-helix-loop-helix (bHLH) transcription factor family, which regulates muscle determination and differentiation in vertebrates. While it is now well established that the MyoD gene is regulated by Sonic hedgehog, Wnts, and other signals, it is not known how MyoD transcription is initiated and maintained in response to these signals. We have investigated the cis control of MyoD expression to identify and characterize the DNA targets that mediate MyoD transcription in embryos. By monitoring lacZ reporter gene expression in transgenic mice, we show that regulatory information contained in 24 kb of human MyoD 5' flanking sequence is sufficient to accurately control MyoD expression in embryos. Previous studies have identified two muscle-specific regulatory regions upstream of MyoD, a 4-kb region centered at -20 kb (designated fragment 3) that contains a highly conserved 258-bp core enhancer sequence, and a more proximal enhancer at -5 kb, termed the distal regulatory region (DRR), that heretofore has been identified only in mice. Here, we identify DRR-related sequences in humans and show that DRR function is conserved in humans and mice. In addition, transcriptional activity of MyoD 5' flanking sequences in somites and limb buds is largely a composite of the individual specificities of the two enhancers. Deletion of fragment 3 resulted in dramatic but temporary expression defects in the hypaxial myotome and limb buds, suggesting that this regulatory region is essential for proper temporal and spatial patterning of MyoD expression. These data indicate that regulatory sequences in fragment 3 are important targets of embryonic signaling required for the initiation of MyoD expression.

Animals↗

PubMed2001

Coexpression of endothelial PAS protein 1 with essential angiogenic factors suggests its involvement in human vascular development.

Endothelial PAS protein 1 (EPAS1) is a bHLH-PAS transcription factor involved in cellular response to hypoxia. Its precise role in angiogenesis is unclear, but several genes essential to vascular development, including those encoding vascular endothelial growth factor (VEGF), its receptor VEGFR-2 and Tie2, are thought to be targets of EPAS1. To investigate whether this transcription factor and its putative targets were expressed concomitantly, we performed in situ hybridization on serial adjacent sections of human embryos at gestational ages of 3 to 6 weeks. We studied expression of the genes encoding EPAS1, VEGF, VEGFR-1, and -2, Tie2, and its ligands, angiopoietin (Ang) 1 and 2. We also compared these expression profiles with that of hypoxia-inducible factor 1alpha (HIF1alpha). EPAS1 transcripts were detected in several types of endothelial cell: in blood vessels walls, the endocardium, the glomeruli of the mesonephros, and the sinusoids of the liver. In these endothelial cells, expression of EPAS1 systematically or partly coincided with Tie2 and the VEGF receptors expression. There was also some overlap between the sites of synthesis of EPAS1 and VEGF mRNAs, principally in hepatocytes and sympathetic ganglion cells. In addition, we found that EPAS1 and HIF1alpha transcripts were often colocalized, suggesting a functional redundancy of these two transcription factors during development. These observations are consistent with transactivation by EPAS1 of the expression of its putative target genes during embryogenesis, suggesting that this transcription factor is involved in human angiogenesis. They provide evidence that EPAS1 is involved in the regulation of vascular maturation, remodeling, or stabilization rather than in the early steps of embryonic angiogenesis.

Angiogenesis Inducing Agents↗

PubMed2002

Dynamic expression of chicken cMeso2 in segmental plate and somites.

Abstract Somitogenesis in vertebrates involves prepatterning of paraxial mesoderm into somitomeres, establishing of anteroposterior polarity within somite primordia, and boundary formation between individual somites. cMeso2 is a newly identified chicken gene encoding a bHLH transcription factor, which is expressed in a transient stripe pattern in anterior presomitic mesoderm before segmentation of somites. The expression pattern overlaps with that of cMeso1 and correlates in time with the formation cycle of somites, suggesting that it may have a role in this process. Unlike its homologues in other organisms cMeso2 transcripts in chicken locate to the posterior aspects of somitomeres and constitute a marker for the caudal half of somites. Initiation of cMeso2 expression in presomitic mesoderm as well as its maintenance appears to be independent from influences by surrounding tissues, suggesting that it is part of the intrinsic program underlying segmentation. Although cMeso1 contains a C-terminal activator domain that can be transferred onto an independent DNA-binding domain, no evidence for such a transactivator domain can be found in cMeso2. In contrast, cMeso2 exerts transcriptional inhibition when coexpressed with the cMeso1 transactivator and seems to contain a repressor domain. Thus, cMeso1 and cMeso2 may function in an antagonistic manner during somitogenesis.

Amino Acid Sequence↗

PubMed2004

Dynamic regulation of the Stra13/Sharp/Dec bHLH repressors in mammary epithelium.

Mammary gland development is a dynamic process involving cyclical proliferation, cellular differentiation, and cell death. In this study, we have determined that expression of the Stra13/Sharp/Dec basic helix-loop-helix (bHLH) family is dynamically regulated in mammary epithelium. In cultured HC11 cells, epidermal growth factor (EGF) treatment rapidly induces Stra13 protein accumulation, which is blocked by the synthetic glucocorticoid, dexamethasone. Neither the induction of Stra13 by EGF nor its repression by dexamethasone correlates with changes in Stra13 mRNA levels. During mouse mammary gland development in vivo, Stra13 is highly expressed in epithelial ducts during puberty, and strongly induced in both ducts and alveoli during early involution, while the related Sharp-1 gene is highly expressed only during late stages of involution. Together, these data indicate that Stra13/Dec/Sharp-family bHLH repressors are dynamically regulated during mammary gland development and may function to regulate apoptosis in this tissue.

Animals↗

PubMed2005

The basic helix-loop-helix factor Hand 2 regulates autonomic nervous system development.

Mammalian autonomic nervous system (ANS) development requires the combinatorial action of a number of transcription factors, which include Mash 1, Phox 2b, and GATA 3. Here we show that the bHLH transcription factor, Hand 2 (dHAND), is expressed concurrently with Mash 1 during sympathetic nervous system (SNS) development and that the expression of Hand 2 is not dependent on Mash 1. This suggests that these two bHLH factors work in parallel during SNS development. We also show that ectopic expression of Hand 2 activates the neuronal program and promotes the acquisition of a phenotype corresponding to peripheral neurons including neurons of the SNS lineage in P19 embryonic carcinoma cells. We propose that Hand 2 works in parallel with other members of the transcriptional network to regulate ANS developmental but can ectopically activate the program by a cross-regulatory mechanism that includes the activation of Mash 1. We show that this function is dependent on its interaction with the histone acetyltransferase p300/CBP, indicating that Hand 2 functions to promote ANS development as part of a larger transcriptional complex.

Animals↗

PubMed2005

Zebrafish id2 developmental expression pattern contains evolutionary conserved and species-specific characteristics.

The inhibitor of differentiation or inhibitor of DNA binding (Id) family are members of the helix-loop-helix (HLH) group of transcription factors that play important roles in cell proliferation, differentiation, cell cycle control, and apoptosis. They modulate the formation of active class A-class B basic HLH (bHLH) complexes. Ids lack the amino-terminal associated basic region necessary for DNA binding, thus sequestering the class A factors, inhibiting the formation of active class A-class B heterodimers and, therefore, are considered to act as dominant-negative regulators of differentiation pathways. We isolated zebrafish id2, and its expression during development was characterized. id2, in addition to regions of expression detected in Xenopus and mice, is also expressed in the tegmentum; midbrain-hindbrain boundary; cerebellum; rhombomeres 2,3,4,6; notochord; and corpuscles of Stannius. Furthermore, we show that expression of id2 is repressed in mind bomb mutants, suggesting a role of Notch upstream of Id2.

Amino Acid Sequence↗

PubMed2006

Basic helix-loop-helix gene Hes6 delineates the sensory hair cell lineage in the inner ear.

The basic helix-loop-helix (bHLH) gene Hes6 is known to promote neural differentiation in vitro. Here, we report the expression and functional studies of Hes6 in the inner ear. The expression of Hes6 appears to be parallel to that of Math1 (also known as Atoh1), a bHLH gene necessary and sufficient for hair cell differentiation. Hes6 is expressed initially in the presumptive hair cell precursors in the cochlea. Subsequently, the expression of Hes6 is restricted to morphologically differentiated hair cells. Similarly, the expression of Hes6 in the vestibule is in the hair cell lineage. Hes6 is dispensable for hair cell differentiation, and its expression in inner ear hair cells is abolished in the Math1-null animals. Furthermore, the introduction of Hes6 into the cochlea in vitro is not sufficient to promote sensory or neuronal differentiation. Therefore, Hes6 is downstream of Math1 and its expression in the inner ear delineates the sensory lineage. However, the role of Hes6 in the inner ear remains elusive.

Animals↗

PubMed2006

The zebrafish bHLH PAS transcriptional regulator, single-minded 1 (sim1), is required for isotocin cell development.

A wide range of physiological and behavioral processes, such as social, sexual, and maternal behaviors, learning and memory, and osmotic homeostasis are influenced by the neurohypophysial peptides oxytocin and vasopressin. Disruptions of these hormone systems have been linked to several neurobehavioral disorders, including autism, Prader-Willi syndrome, affective disorders, and obsessive-compulsive disorder. Studies in zebrafish promise to reveal the complex network of regulatory genes and signaling pathways that direct the development of oxytocin- and vasopressin-like neurons, and provide insight into factors involved in brain disorders associated with disruption of these systems. Isotocin, which is homologous to oxytocin, is expressed early, in a simple pattern in the developing zebrafish brain. Single-minded 1 (sim1), a member of the bHLH-PAS family of transcriptional regulatory genes, is required for terminal differentiation of mammalian oxytocin cells and is a master regulator of neurogenesis in Drosophila. Here we show that sim1 is expressed in the zebrafish forebrain and is required for isotocin cell development. The expression pattern of sim1 mRNA in the embryonic forebrain is dynamic and complex, and overlaps with isotocin expression in the preoptic area. We provide evidence that the role of sim1 in zebrafish neuroendocrine cell development is evolutionarily conserved with that of mammals.

Animals↗

PubMed2006

Math6 expression during kidney development and altered expression in a mouse model of glomerulosclerosis.

Math6 is a tissue-restricted member of the Atonal family of basic helix-loop-helix (bHLH) transcription factors and has been implicated in specification and differentiation of cell lineages in the brain. We identify here Math6 as a podocyte-expressed bHLH protein that was down-regulated in human immunodeficiency virus-associated nephropathy (HIVAN); a collapsing glomerulopathy characterized by podocyte dedifferentiation. Early in metanephric development, Math6 was expressed in metanephric mesenchyme but not ureteric bud-derived cells, with overall Math6 expression most abundant in the nephrogenic zone, including developing glomeruli. In adult kidney, Math6 expression was restricted to podocytes. In adult podocyte cell lines and kidneys from the transgenic mouse model of HIVAN, Math6 podocyte expression was reduced concurrent with previously reported reductions in Nephrin and Synaptopodin expression, suggesting a correlation between the loss of Math6 expression and typical podocyte terminal differentiation markers. These studies suggest that Math6 may participate in kidney development and may be a permissive factor for podocyte differentiation.

Amino Acid Sequence↗

PubMed2007

Mash1 regulates the development of C cells in mouse thyroid glands.

In mammals, the ultimobranchial body derived from the fourth pharyngeal pouch gives rise to thyroid C cells. The C cells of newborn mice are immunoreactive for calcitonin, calcitonin gene-related peptide (CGRP), protein gene product (PGP) 9.5 and NeuroD, and transiently exhibit the neuronal markers TuJ1 and somatostatin during fetal development. The basic helix-loop-helix (bHLH) transcription factor Mash1 plays a role in the differentiation of autonomic neurons. We show that in wild-type mouse embryos, Mash1 is expressed in the ultimobranchial body at embryonic day (E) 12.5, when the body is located close to the great arch arteries. It is also expressed in the ultimobanchial body fused with the thyroid lobe at E 13.5. Targeted disruption of Mash1 resulted in the absence of C cells in the mouse thyroid glands, since cells displaying the C-cell markers and expressing NeuroD were not detected during fetal development or at birth. The failure of C-cell formation in the null mutant thyroids was also confirmed by electron microscopy. While the formation and migration of the ultimobranchial body were not affected in the Mash1 null mutants, at E 12.5-E 13.5 both the ultimobranchial body located close to the arteries and the organ populating the thyroid lobe exhibited a marked increase in apoptotic cell numbers. Thus, in the mutant mice, the ultimobranchial body fails to complete its differentiation program and finally dies. These results indicate that Mash1 enhances survival of the C-cell progenitors by inhibiting apoptosis.

Animals↗

PubMed2006

Genetic targeting of principal neurons in neocortex and hippocampus of NEX-Cre mice.

Conditional mutagenesis permits the cell type-specific analysis of gene functions in vivo. Here, we describe a mouse line that expresses Cre recombinase under control of regulatory sequences of NEX, a gene that encodes a neuronal basic helix-loop-helix (bHLH) protein. To mimic endogenous NEX expression in the dorsal telencephalon, the Cre recombinase gene was targeted into the NEX locus by homologous recombination in ES cells. The Cre expression pattern was analyzed following breeding into different lines of lacZ-indicator mice. Most prominent Cre activity was observed in neocortex and hippocampus, starting from around embryonic day 11.5. Within the dorsal telencephalon, Cre-mediated recombination marked pyramidal neurons and dentate gyrus mossy and granule cells, but was absent from proliferating neural precursors of the ventricular zone, interneurons, oligodendrocytes, and astrocytes. Additionally, we identified formerly unknown domains of NEX promoter activity in mid- and hindbrain. The NEX-Cre mouse will be a valuable tool for behavioral research and the conditional inactivation of target genes in pyramidal neurons of the dorsal telencephalon.

Animals↗

PubMed2006

The chicken Ig light chain 3'-enhancer is essential for gene expression and regulates gene conversion via the transcription factor E2A.

Expression of the rearranged chicken immunoglobulin light chain (IgL) gene is regulated by a V gene promoter, a matrix attachment region (MAR) in the J-C intron and an enhancer downstream of the Ig constant region. Using knockout analysis, we demonstrate that the 3'-enhancer is not only required for gene activation but is also essential for the maintenance of gene expression. Deletion of the MAR on the other hand increases IgL transcription, indicating that the MAR acts as negative regulator. We demonstrate that Id1 and Id3, dominant-negative regulators of basic-region helix-loop-helix (bHLH) transcription factors, are able to reduce chicken IgL 3'-enhancer activity in transient assays and strongly reduce the rate of gene conversion (GC) in DT40 clone 18 cells. Conversely, overexpression of avian E47, a bHLH transcription factor, leads to a dramatic increase in GC rates independent of IgL or activation-induced cytidine deaminase RNA levels. Thus, E47 is the first transcription factor to activate GC without an apparent increase in transcription.

Animals↗

PubMed2004

Neurogenic phenotypes induced by RNA interference with bHLH genes of the Enhancer of split complex of Drosophila melanogaster.

The Enhancer of split gene complex [E(spl)-C] of Drosophila melanogaster harbors seven highly related genes encoding transcriptional regulators with a basic helix-loop-helix (bHLH) domain. They are activated by the Notch signaling pathway in order to inhibit proneural gene activity, for example, during neurogenesis in the developing embryo. The E(spl) proteins are at least partly redundant, despite some remarkable differences in their expression patterns. We attempted to address the degree of redundancy by means of RNA interference. We find a quantitative correlation between the degree of a neurogenic phenotype and the number of genes affected. Surprisingly, interference with m3 results in a high rate of mortality which cannot be reproduced by genetic mutation. Most likely, m3 dsRNA interferes with unrelated genes involved in other aspects of embryonic development.

Animals↗

PubMed2005

Cre/loxP-mediated inactivation of the bHLH transcription factor gene NeuroD/BETA2.

NeuroD/Beta2 is a basic helix-loop-helix (bHLH) transcription factor with important functions during development of the pancreas and the nervous system. NeuroD null mutant mice die perinatally due to diabetes caused by impaired differentiation of pancreatic endocrine cells. Additionally, null mutants display severe defects in the formation of cerebellar and hippocampal granule cells, inner ear sensory neurons, and retinal photoreceptor cells. For spatio-temporally restricted inactivation of the NeuroD gene, we generated conditional mouse mutants by flanking the NeuroD coding region with loxP sites. Homozygous NeuroD(loxP) mutant mice are fully viable and express normal levels of NeuroD mRNA and protein. Breeding NeuroD(loxP) mice to Tg(malpha6-Cre)B1LFR mice that express Cre recombinase under control of the GABA(A) receptor alpha6 subunit promoter resulted in efficient inactivation of the NeuroD gene in post-migratory cerebellar granule cells and a subset of brainstem nuclei. The NeuroD(loxP) mouse mutant will be a valuable tool to study the developmental and adult function of NeuroD in nervous system and pancreas.

Animals↗

PubMed2006

Olig gene function in CNS development and disease.

Olig1 and Olig2 encode basic helix-loop-helix (bHLH) transcription factors that are expressed in both the developing and mature vertebrate central nervous system. While numerous studies have established critical functions for Olig genes during the formation of motor neurons and oligodendrocytes of the ventral neural tube, their roles at later stages of development and in adulthood have remained relatively obscure. Recent studies, however, reveal that in the fetal dorsal spinal cord and neural progenitor cells of the adult brain, Olig expression continues to mark, and may regulate, the formation of oligodendroglia. Studies of Olig expression in human brain tumors and repair of demyelinating lesions suggest the possibility of additional functions in a variety of neurological diseases.

Animals↗

PubMed2006

HEY2 mutations in malformed hearts.

The basic helix-loop-helix (bHLH) transcription factor Hey2 (gridlock) is an important determinant of mammalian heart development, but its role in human ventricular septal defects is unknown. Hey2 functions as a repressor through the bHLH domain. By direct sequencing, we analyzed the sequences encoding the bHLH domain of the human HEY2 in 52 explanted hearts of unrelated patients with complex cardiac malformations, notably ventricular (VSD) and atrioventricular septal defects (AVSD). We found three nonsynonymous mutations, namely, c.286A>G (p.Thr96Ala), c.293A>C (p.Asp98Ala), and c.299T>C (p.Leu100Ser) affecting the second helix of HEY2 in the diseased cardiac tissues of two patients with AVSD. This result suggests a possible role of HEY2 in the regulation of ventricular septation in humans. Since the two AVSD patients carried also binding domain mutations in other cardiac-specific transcription factors, e.g. NKX2-5, TBX5, and GATA4, breakdown of combinatorial interactions of transcription factors may have contributed to the complexity of their cardiac malformations.

Basic Helix-Loop-Helix Proteins↗