Mediation of NGF signaling by post-translational inhibition of HES-1, a basic helix-loop-helix repressor of neuronal differentiation

The development of the vertebrate nervous system depends upon striking a balance between differentiating neurons and neural progenitors in the early embryo. Our findings suggest that the homeodomain-containing gene Xdbx regulates this balance by maintaining neural progenitor populations within specific regions of the neuroectoderm. In posterior regions of the Xenopus embryo, Xdbx is expressed in a bilaterally symmetric stripe that lies at the middle of the mediolateral axis of the neural plate. This stripe of Xdbx expression overlaps the expression domain of the proneural basic/helix-loop-helix-containing gene, Xash3, and is juxtaposed to the expression domains of Xenopus Neurogenin related 1 and N-tubulin, markers of early neurogenesis in the embryo. Xdbx overexpression inhibits neuronal differentiation in the embryo and when co-injected with Xash3, Xdbx inhibits the ability of Xash3 to induce ectopic neurogenesis. One role of Xdbx during normal development may therefore be to restrict spatially neuronal differentiation within the neural plate, possibly by altering the neuronal differentiation function of Xash3.

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Overexpression of Stra13, a novel retinoic acid-inducible gene of the basic helix-loop-helix family, inhibits mesodermal and promotes neuronal differentiation of P19 cells

Genes & Development ◽

10.1101/gad.11.16.2052 ◽

1997 ◽

Vol 11 (16) ◽

pp. 2052-2065 ◽

Cited By ~ 162

Author(s):

M. Boudjelal ◽

R. Taneja ◽

S. Matsubara ◽

P. Bouillet ◽

P. Dolle ◽

...

Keyword(s):

Retinoic Acid ◽

Neuronal Differentiation ◽

P19 Cells ◽

Basic Helix Loop Helix ◽

Helix Loop Helix ◽

Inducible Gene

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Regulation of hippocampal neuronal differentiation by the basic helix-loop-helix transcription factors HES-1 and MASH-1

Journal of Neuroscience Research ◽

10.1002/(sici)1097-4547(19990501)56:3<229::aid-jnr2>3.0.co;2-z ◽

1999 ◽

Vol 56 (3) ◽

pp. 229-240 ◽

Cited By ~ 36

Author(s):

Paul Castella ◽

John A. Wagner ◽

Michael Caudy

Keyword(s):

Transcription Factors ◽

Neuronal Differentiation ◽

Basic Helix Loop Helix ◽

Helix Loop Helix

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The bHLH gene Hes6, an inhibitor of Hes1, promotes neuronal differentiation

Development ◽

10.1242/dev.127.13.2933 ◽

2000 ◽

Vol 127 (13) ◽

pp. 2933-2943 ◽

Cited By ~ 7

Author(s):

S. Bae ◽

Y. Bessho ◽

M. Hojo ◽

R. Kageyama

Keyword(s):

Cell Differentiation ◽

Neuronal Differentiation ◽

Rod Photoreceptor ◽

Bhlh Gene ◽

Basic Helix Loop Helix ◽

Helix Loop Helix ◽

Differentiated Cells ◽

Loop Region ◽

The Family ◽

Enhancer Of Split

We have isolated the basic helix-loop-helix (bHLH) gene Hes6, a novel member of the family of mammalian homologues of Drosophila hairy and Enhancer of split. Hes6 is expressed by both undifferentiated and differentiated cells, unlike Hes1, which is expressed only by the former cells. Hes6 alone does not bind to the DNA but suppresses Hes1 from repressing transcription. In addition, Hes6 suppresses Hes1 from inhibiting Mash1-E47 heterodimer and thereby enables Mash1 and E47 to upregulate transcription in the presence of Hes1. Furthermore, misexpression of Hes6 with retrovirus in the developing retina promotes rod photoreceptor differentiation, like Mash1, in sharp contrast to Hes1, which inhibits cell differentiation. These results suggest that Hes6 is an inhibitor of Hes1, supports Mash1 activity and promotes cell differentiation. Mutation analysis revealed that Hes1- and Hes6-specific functions are, at least in part, interchangeable by alteration of the loop region, suggesting that the loop is not simply a nonfunctional spacer but plays an important role in the specific functions.

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Regulation of neurogenesis by interactions between HEN1 and neuronal LMO proteins

Development ◽

10.1242/dev.127.2.425 ◽

2000 ◽

Vol 127 (2) ◽

pp. 425-435 ◽

Cited By ~ 2

Author(s):

J. Bao ◽

D.A. Talmage ◽

L.W. Role ◽

J. Gautier

Keyword(s):

Neuronal Differentiation ◽

Transcriptional Activity ◽

Expression Patterns ◽

Dorsal Side ◽

Neural Plate ◽

Basic Helix Loop Helix ◽

Helix Loop Helix ◽

Human Genes ◽

Early Neurogenesis

Basic-helix-loop-helix transcription factors regulate neurogenesis and neuronal differentiation by as yet unknown mechanisms. We show that an embryonic neuronal-specific basic-helix-loop-helix protein, HEN1 (also known as NSCL1 or NHLH), interacts with ‘LIM only’ proteins. Examination of the expression patterns of XHEN1 and XLMO-3, the Xenopus homologues of these human genes, reveals extensive overlap during early neurogenesis: at the onset of gastrulation on the dorsal side of the blastopore lip and, subsequently, in the prospective neural plate. Binding of XLMO-3 increases the transcriptional activity of XHEN1 in vivo. Co-expression of these two genes in Xenopus embryos induces a cascade of expression of neuronal-specific basic-helix-loop-helix proteins that leads to neuronal differentiation. We propose that XHEN1, in concert with XLMO-3, is a critical regulator of neurogenesis.

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Basic Helix-Loop-Helix Proteins Bind to TrkB and p21Cip1 Promoters Linking Differentiation and Cell Cycle Arrest in Neuroblastoma Cells

Molecular and Cellular Biology ◽

10.1128/mcb.24.7.2662-2672.2004 ◽

2004 ◽

Vol 24 (7) ◽

pp. 2662-2672 ◽

Cited By ~ 60

Author(s):

Yuhui Liu ◽

Mario Encinas ◽

Joan X. Comella ◽

Martí Aldea ◽

Carme Gallego

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Neuronal Differentiation ◽

Ectopic Expression ◽

Neurotrophin Receptor ◽

Basic Helix Loop Helix ◽

Helix Loop Helix ◽

Cycle Arrest ◽

E Box ◽

Bhlh Proteins

ABSTRACT Differentiation of precursor into specialized cells involves an increasing restriction in proliferative capacity, culminating in cell cycle exit. In this report we used a human neuroblastoma cell line to study the molecular mechanisms that coordinate cell cycle arrest and neuronal differentiation. Exposure to retinoic acid (RA), a differentiation agent in many cell types, causes an upregulation of neurotrophin receptor TrkB and the cyclin kinase inhibitor p21Cip1 at a transcriptional level. Full transcriptional activation of these two genes requires canonical E-box sequences found in the TrkB and p21Cip1 promoters. As reported for other E-box-regulated promoters, ectopic expression of E47 and E12 basic helix-loop-helix (bHLH) proteins enhances RA-dependent expression of TrkB and p21Cip1 , whereas the inhibitory HLH Id2 exerts opposite effects. In addition, ectopic expression of E47 and NeuroD, a neuronal bHLH protein, is able to activate TrkB transcription in the absence of RA. More importantly, we show that E47 and NeuroD proteins bind the TrkB and p21Cip1 promoter sequences in vivo. Since they establish a direct transcriptional link between a cell cycle inhibitor, p21Cip1 , and a neurotrophic receptor, TrkB, bHLH proteins would play an important role in coordinating key events of cell cycle arrest and neuronal differentiation.

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