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

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PubMed1999

Deconstructing cell determination: proneural genes and neuronal identity.

Vertebrates express scores of bHLH proteins during neural development. Earlier studies inspired by the established role of "proneural" genes in fly neurogenesis, as well as by the vertebrate bHLH myogenic program, focused on the reconstruction of bHLH gene cascades, which are thought to control successive steps leading to neuronal differentiation. Little attention has been paid thus far to the relationship between the diversity of neural bHLH genes and the diversity of neuronal phenotypes. This article reviews recent evidence that, akin to their fly counterparts, vertebrate neural bHLH genes probably confer not only "generic" neuronal properties, but also neuronal type-specific properties, inextricably linking neural determination and the specification of neuronal identity. We also speculate on the relations between positional information and gene activity, and on the evolutionary significance of the diversity of bHLH genes.

Animals↗

PubMed2000

The pan-neural bHLH proteins DEADPAN and ASENSE regulate mitotic activity and cdk inhibitor dacapo expression in the Drosophila larval optic lobes.

Developmental regulators and cell cycle regulators have to interface in order to ensure appropriate cell proliferation during organogenesis. Our analysis of the roles of the pan-neural genes deadpan and asense defines critical roles for these genes in regulation of mitotic activities in the larval optic lobes. Loss of deadpan results in reduced cell proliferation, while ectopic deadpan expression causes over-proliferation. In contrast, loss of asense results in increased proliferation, while ectopic asense expression causes reduced proliferation. Consistent with these observations endogenous Deadpan is expressed in mitotic areas of the optic lobes, and endogenous Asense is expressed in cells that will become quiescent. Altered Deadpan or Asense expression results in altered expression of the cyclin dependent kinase inhibitor gene dacapo. Thus, regulation of mitotic activity during optic lobe development may, at least in part, involve deadpan and asense mediated regulation of the cyclin dependent kinase inhibitor gene dacapo. genesis 26:77-85, 2000.

Animals↗

PubMed2000

Xenopus Hand2 expression marks anterior vascular progenitors but not the developing heart.

We have isolated cDNAs encoding the bHLH protein Hand2 in the amphibian Xenopus laevis and analysed Hand2 expression in early development from the onset of gastrulation to feeding tadpole stages. XHand2 is expressed in the branchial arch mesenchyme and also in small bilateral populations of cells in the anterior, ventrolateral region of early tailbud embryos. At later stages, these punctate Hand2-expressing cells are located at the sites of the forming common cardinal veins, suggesting that they may constitute progenitors of vascular smooth muscle cells. Other Hand2-expressing cells are also associated with further components of the forming anterior vasculature but are not detected in mature blood vessels. Interestingly, no myocardial expression of XHand2 can be detected in the developing tadpole heart, in marked contrast to results obtained with chick and mouse embryos.

Amino Acid Sequence↗

PubMed2000

The basic helix-loop-helix transcription factor E2-2 is involved in T lymphocyte development.

E2A, HEB and E2-2 genes encode a group of basic helix-loop-helix (bHLH) transcription factors that are structurally and functionally similar. Deletion of the genes encoding either of these proteins leads to early lethality and a block in B lymphocyte development. Evidence for a function in T lymphocyte development has, however, only been reported for E2A and HEB. To further elucidate the role of E2-2 at developmental stages that have proven difficult to study due to the early lethality phenotype of mice defective in E2-2, we generated and analyzed mice conditionally mutated in the E2-2 gene. These mice are mosaic with respect to E2-2 expression, consisting of cells with either one functional and one null mutated E2-2 allele or two null mutated alleles. Using this experimental model, we find that cells with a homozygous null mutated E2-2 gene are under-represented in B lymphocyte as well as T lymphocyte cell lineages as compared to other hematopoietic or non-hematopoietic cell lineages. Our data suggests that E2-2 deficiency leads to a partial block in both B and T lymphocyte development. The block in T cell development appears to occur at an early stage in differentiation, since skewing in the mosaicism is observed already in CD4+8+ double-positive thymocytes.

Alleles↗

PubMed2002

The pT alpha promoter and enhancer are direct targets for transactivation by E box-binding proteins.

The pre-T alpha (pT alpha) gene encodes a protein that forms the pre-TCR together with the newly expressed TCR beta chain during a defined stage of early T cell development. The restricted expression of this gene has been suggested to depend on a promoter and an enhancer element containing E boxes, which are potential binding sites for basic helix-loop-helix (bHLH) proteins. We here report that increased expression of E47 and E12 mRNA in CD4(-)CD8(-)TCR(-) thymocytes correlates with the initiation of pT alpha transcription. Furthermore, electrophoretic mobility shift assays suggested that E47 binds directly to both the pT alpha promoter and enhancer in vitro. Ectopic expression of E47 in non-lymphoid HeLa cells resulted in a dose- and template-dependent activation of these control elements. In addition to this, ectopic expression of E47 in combination with the ets-protein Pu.1 and/or the Pu.1-interacting protein(Pip-1), resulted in a synergistic effect on the activity of the pT alpha control elements. Thus, we suggest that E47, Pu.1 and Pip-1 are directly involved in the regulation of pT alpha expression in early T cell development.

Animals↗

PubMed2005

Disruption of a brain transcription factor, NPAS3, is associated with schizophrenia and learning disability.

A mother and daughter diagnosed with schizophrenia and schizophrenia co-morbid with mild learning disability, respectively, possess a balanced reciprocal translocation t(9,14)(q34.2;q13). Fluorescence in situ hybridization (FISH) with YAC, BAC, and cosmid probes indicate that the chromosome 14q13 breakpoint disrupts a large gene, NPAS3, encoding a CNS expressed transcription factor of the basic helix-loop-helix PAS (bHLH-PAS) gene family. By analogy with other members of the bHLH-PAS family, the putative truncated protein generated from the disrupted gene locus may have a dominant negative effect. The 14q13 region was previously identified by a linkage study of an inherited neurodegenerative condition, idiopathic basal ganglia calcification (IBGC or Fahr syndrome, OMIM:213600/606656), which is often co-morbid with psychosis. Sequencing of the gene in a third patient diagnosed with IBGC, schizophrenia, and mild learning disability did not reveal functional mutations.

Abnormalities, Multiple↗

PubMed2007

Association between the 5q31.1 gene neurogenin1 and schizophrenia.

Multiple lines of evidence suggest that schizophrenia results from aberrant neurodevelopment. The neurogenin1 gene (neurog1) consists of a single 1,666 bp exon that encodes a basic helix-loop-helix (bHLH) transcription factor that causes neuronal differentiation and induces cortical and glutamatergic differentiation programs. Because of its function and its location in 5q31.1, which has been linked to schizophrenia in multiple samples, we tested it for association with the disorder. We sequenced neurog1 in 25 affected subjects from the Irish Study of High-Density Schizophrenia Families. We observed a 5'-UTR SNP at position -60, already present in databases as rs8192558, and tested it along with rs2344485, rs8192559, and rs2344484. Narrow, intermediate, and broad diagnostic definitions were used. The major alleles of rs8192558 and rs2344484 were over-transmitted to affected subjects using both Pedigree Disequilibrium Test (PDT) (0.01 < or = P < or = 0.06) and FBAT (0.02 < or = P < or = 0.07). A haplotype consisting of the major alleles of all four SNPs was significantly over-transmitted in FBAT to the broad definition (P = 0.049), with trend significance to the narrow and intermediate definitions, and with trend significance in PDT. In confirmatory tests using 657 cases and 411 controls, this haplotype was slightly but not significantly over-represented in cases (81% vs. 77%, P = 0.21). These results, along with a priori evidence for the involvement of neurog1 in neurodevelopment, suggest that variants in neurog1 might have a small effect on susceptibility to schizophrenia. This gene should be tested in additional and larger samples.

Basic Helix-Loop-Helix Proteins↗

PubMed2004

Combinatorial transcriptional interaction within the cardiac neural crest: a pair of HANDs in heart formation.

The cardiac neural crest cells migrate from the rostral dorsal neural folds and populate the branchial arches, which contribute directly to the cardiac-outflow structures. Although neural crest cell specification is associated with a number of morphogenic factors, little is understood about the mechanisms by which transcription factors actually implement the transcriptional programs that dictate cell migration and later the differentiation into the proper cell types within the great vessels and the heart. It is clear from genetic evidence that members of the paired box family and basic helix-loop-helix (bHLH) transcription factors from the twist family of proteins are expressed in and play an important function in cardiac neural crest specification and differentiation. Interestingly, both paired box and bHLH factors can function as dimers and, in the case of twist family bHLH factors, partner choice can clearly dictate a change in transcriptional program. The focus of this review is to consider what role the protein-protein interactions of these transcription factors may play in determining cardiac neural crest specification and differentiation, and how genetic alteration of transcription factor stoichiometry within the cell may reflect more than a simple null event.

Animals↗

PubMed2005

A twisted hand: bHLH protein phosphorylation and dimerization regulate limb development.

Saethre-Chotzen syndrome (SCS), a human autosomal dominant condition with limb defects and craniosynostosis, is caused by haploinsufficiency of TWIST1, a basic helix-loop-helix (bHLH) transcription factor. Until recently, the molecular pathogenesis of the limb defects in SCS has not been well understood. Now, Firulli et al.1 show in mouse and chick that ectopic expression of a related bHLH protein, Hand2, results in phenocopies of the limb defects caused by Twist1 loss-of-function mutations. These two proteins interact in a dosage-dependent antagonistic manner, and both can be regulated through phosphorylation at conserved helix I amino acid residues. These findings provide an important link between the misregulation of Twist1 dimerization and the limb phenotypes observed in SCS.

Animals↗

PubMed2005

Role of DNA sequence in the binding specificity of synthetic basic-helix-loop-helix domains.

The basic helix-loop-helix (bHLH) domain defines a class of transcription factors that are essential for the regulation of many genes involved in cell differentiation and development. To determine the role of the DNA sequence in driving dimerization specificity of bHLH transcription factors, we analyzed the DNA sequence in and around a consensus hexanucleotide binding site (E-box). The bHLH domains of two transcription factors, E12 and TAL1, were chemically synthesized. The minimal DNA binding domain for both the E12 homodimer and the E12-TAL1 heterodimer was determined, thereby extending the E-box by two base pairs. Additional studies indicate that the presence of a thymine in the first flanking position 5' to the E-box prevents DNA binding of both dimer complexes. The presence of a thymine or cytosine in a flanking position two bases 5' to the E-box decreases the affinity for the E12 homodimer twofold but completely inactivates DNA binding for the E12-TAL1 heterodimer. Access to synthetic DNA and protein enabled the analysis of specific interactions between a conserved arginine residue in the basic helix of each bHLH domain and adenine in a flanking position two bases 5' to the E-box. Our results indicate a key role of the DNA sequence in driving dimerization specificity among bHLH transcription factors.

Amino Acid Sequence↗

PubMed2004

The basic helix-loop-helix transcription factor neuroD is expressed in the rod lineage of the teleost retina.

Persistent rod genesis in the retinas of teleost fish was first described over 2 decades ago, but little is known regarding the underlying genetic and molecular mechanisms that govern this phenomenon. Because of its function in the developing mammalian retina and persistently mitotic adult tissues, we sought to characterize the cellular expression of the basic helix-loop-helix (bHLH) transcription factor neuroD in the persistently neurogenic retina of adult teleosts. We show here that, in the adult retina of the goldfish, neuroD is expressed by putative amacrine cells, nascent cones, and the mitotically active cells of the rod lineage. neuroD is the first gene shown to be expressed by rod precursors, the immediate antecedents of rod photoreceptors. In contrast to the vertebrate classes described previously, neuroD is not expressed in multipotent progenitors in the teleost retina. Combining neuroD in situ hybridizations with cell-cycle-specific markers suggests that, in rod precursors, neuroD expression is cell cycle specific.

Animals↗

PubMed2004

Expression of Islet1 marks the sensory and neuronal lineages in the mammalian inner ear.

Several basic helix-loop-helix (bHLH) genes have been shown to be essential for the generation of the auditory sensory hair cells or the spiral ganglion (SG) neurons that innervate the hair cells in the cochlea, as well as a variety of cell types in the other nervous systems. However, it remains elusive what cellular context-dependent mechanisms confer the inner ear-specific neuronal or sensory competency/identities. We explored the possibility that one of the mechanisms responsible for generating cellular diversity in the nervous system through cooperative action of bHLH and LIM-homeodomain (LIM-HD) transcriptional factors might also contribute to the inner ear-specific sensory and/or neuronal competency. Here, we show that Islet1 (Isl1), a LIM-HD protein, is expressed early in the otocyst in the region that gives rise to both the auditory sensory organ, the organ of Corti, and SG neurons. Subsequently, the expression of Isl1 is maintained in SG neurons but is transitory in the sensory lineage. At embryonic day 12 (E12) in mice, the expression of Isl1 marks distinctively the ventral portion of the nascent cochlear epithelium encompassing the primordial organ of Corti. At E13, Isl1 is maintained at relatively high levels in the sensory primordium while down-regulated in the other regions of the cochlear duct. As the sensory epithelium starts to differentiate, it is down-regulated in the entire cochlear epithelium. The expression of Isl1 in the developing inner ear reveals an early and likely a common step in the development of both sensory and neuronal lineages of the inner ear, and suggests its potential role in the inner ear-specific sensory and neuronal cell development.

Animals↗

PubMed2007

Dynamic expression of the basic helix-loop-helix transcription factor neuroD in the rod and cone photoreceptor lineages in the retina of the embryonic and larval zebrafish.

NeuroD is a basic helix-loop-helix (bHLH) transcription factor critical for determining neuronal cell fate and regulating withdrawal from the cell cycle. We showed previously that, in goldfish, neuroD is expressed in the rod photoreceptor lineage, and we inferred that neuroD is also expressed in a subset of amacrine cells and nascent cone photoreceptors. Here we extended that study by examining the temporal and spatial expression pattern of neuroD in the embryonic and larval zebrafish and by identifying the cell types that express this gene. NeuroD expression in the developing zebrafish retina is dynamic, spanning early retinogenesis and the maturation of cone photoreceptors. In early retinogenesis neuroD expression expands from a small patch in the ventronasal retina, through the remaining retinal neuroepithelium. As retinogenesis progresses, neuroD expression becomes restricted to amacrine cells, immature cones, and cells of rod and cone lineages. This expression achieves an adult pattern by 96 hours postfertilization (hpf), whereupon the temporal pattern of neuroD expression in central retina is spatially recapitulated at the germinative margin. The cellular pattern of expression suggests that neuroD regulates aspects of rod and cone genesis, but through separate cellular lineages. Furthermore, neuroD is coexpressed with the cone-rod-homeobox transcription factor (Crx) in putative cone progenitors and nascent cone photoreceptors, suggesting that, in the zebrafish retina, as in other vertebrate retinas, similar genetic cascades regulate photoreceptor genesis and maturation.

Animals↗

PubMed2002

Coexpression of SCL and GATA3 in the V2 interneurons of the developing mouse spinal cord.

The differentiation of neural progenitors into the many classes of neurons that exist in the mature spinal cord is a process that relies heavily on the activation of precise combinations of transcription factors. Defining these transcription factor combinations is an important aspect of research in developmental neurobiology that promises to provide incredible insights into the structure, function, and pathology of the central nervous system. The present study aimed to investigate a possible role for the Stem Cell Leukemia (SCL) gene, a basic helix-loop-helix (bHLH) transcription factor gene, in the specification of a population of neural cells in the ventral neural tube. Section RNA in situ hybridisation revealed that SCL is transiently expressed within the V2 postmitotic domain of the developing mouse spinal cord between 10.5 and 13.5 days post coitum. Double-immunofluorescence experiments were subsequently carried out to directly compare the expression of SCL with other V2-specific markers at the cellular level. These experiments revealed that SCL is expressed in a medially restricted subpopulation of GATA-3 producing cells, suggesting a possible role for this factor in the differentiation of the GATA population of V2 interneurons.

Animals↗

PubMed2002

Xath5 regulates neurogenesis in the Xenopus olfactory placode.

Helix-loop-helix (HLH) genes function as important regulators of neurogenesis in both the peripheral and central nervous systems. The olfactory system is an ideal tissue in which to study the role of these genes in regulating the acquisition of neuronal cell fate, particularly that of the olfactory receptor neuron (ORN). Here we describe the expression of several basic HLH (bHLH) and repeat HLH (rHLH) factors during olfactory placode development in Xenopus laevis. Our work reveals that a combination of both bHLH and rHLH genes are sequentially expressed within the nascent olfactory placode during normal development. Moreover, overexpression of the bHLH factor, Xenopus atonal homologue 5 (Xath5), promotes olfactory neural fate independent of cellular proliferation within a restricted domain at the anterior of the embryo. Collectively, our data argue that HLH genes are expressed in a cascade during olfactory placode development and that the activity of an atonal homologue, Xath5, can promote ORN fate but only in the appropriate developmental context.

Animals↗

PubMed2002

Isolation and characterization of Xenopus Hey-1: a downstream mediator of Notch signaling.

Regulation of Notch signaling likely occurs, at least in part, at the level of basic helix-loop-helix (bHLH) transcription factors that function downstream of Suppressor of Hairless (Su(H)) in the Notch pathway. To begin to characterize modulation of Notch signaling during organogenesis, we examined the bHLH transcription factor, XHey-1 (hairy related-1) in early Xenopus laevis embryos. XHey-1 is expressed in numerous tissues during early development including the somites, head, embryonic kidneys, and heart. Importantly, the expression of XHey-1 was significantly altered in response to perturbation of Notch signaling by means of inducible constructs that served to either activate or suppress Notch signaling through Su(H) in a temporally controlled manner.

Animals↗

PubMed2003

Expression and regulation of eHAND during limb development.

eHAND is a bHLH transcription factor with important functions during embryogenesis. Here, we report that eHAND has a dynamic pattern of expression during limb development. In chick embryos, eHAND expression is first observed in the ventral mesoderm of the emerging limb. Its expression is then restricted to an anteroventral area of mesoderm at mid-level in the proximodistal axis. At later stages, expression is observed in the autopod encompassing the ventral tendons of the digits. In mouse embryos, only the anteroventral domain of expression is conserved, the early ventral expression not being detectable and the late pattern of expression differing clearly from that in the chick. A constant feature of all areas of expression is their ventral and anterior localization. Respecification of the anterior mesoderm as occurs secondarily to Sonic hedgehog (SHH) or retinoic acid application to the anterior border leads to down-regulation of eHAND expression. Accordingly, eHAND expression is not detectable in talpid(2) mutant limbs, which are considered to be posteriorized limbs. However, eHAND expression is little modified in oligozeugodactyly, a chick mutant that lacks Shh signaling in the limb but retains certain anteroposterior polarity. Interestingly, eHAND expression is also linked to the ventral identity of the mesoderm and is repressed by the dorsal ectoderm. It is also positively regulated by bone morphogenetic protein signaling, which is also known to participate in dorsoventral patterning. We suggest that eHAND expression may be related to the anteroventral identity of the mesoderm. However, in overexpression experiments using retroviral vectors, only a low percentage of cases (5%) showed phenotypic alterations, consisting of a duplication of digit 2.

Animals↗

PubMed2003

Zebrafish atonal homologue zath3 is expressed during neurogenesis in embryonic development.

Basic helix-loop-helix (bHLH) transcriptional activators function in development of various cell lineages, including the central nervous system. One of the bHLH proteins, Math3/Xath3/NeuroM, was suggested to act as a late proneural gene in the mouse, Xenopus, and chick. Here, we isolated a zebrafish homologue, named zath3, and analyzed its expression pattern in zebrafish embryos. In the neural plate, zath3 is expressed first in the primordia of the tegmentum and trigeminal ganglia and three classes of primary neurons: sensory neurons, interneurons, and motor neurons. During later development, zath3 transcripts were localized along the boundaries of the optic tectum in the midbrain and rhombomeres of the hindbrain. Analyses of zath3 expression in three mid-hindbrain boundary mutants, acerebellar, no isthmus, and spiel-ohne-grensen, indicated that distribution of zath3 mRNAs in the midbrain and hindbrain was dramatically disturbed. In addition, these mutants also affect expression of zath3 in the neuroretina.

Amino Acid Sequence↗