A Role for bHLH Transcription Factors in Retinal Degeneration and Dysfunction

Department of Ophthalmology, Baylor College of Medicine, Houston, Texas 77030, USA.
Advances in Experimental Medicine and Biology (Impact Factor: 1.96). 02/2006; 572:155-61. DOI: 10.1007/0-387-32442-9_23
Source: PubMed


The basic helix loop helix (bHLH) transcription factors collectively mediate cellular differentiation in almost every type
of tissue including the retina (Murre et al. 1989; Jan and Jan 1993; Cepko 1999). Class A factors are ubiquitously expressed throughout mammalian tissue, while the expression
of class B factors are cell type specific. These factors have both a DNA binding domain and helix loop helix domain (HLH)
protein dimerization domain. Class B factors usually heterodimerize with the ubiquitously expressed, bHLH factors, such as
E12/E47. Because of their importance during photoreceptor development, bHLH factors are candidate genes for photoreceptor
degeneration. We have examined the roles of two bHLH factors, both which are expressed during retinal development, but also
share the property of continued expression in the adult retina.

  • Source
    • "Neither of these proteins has been shown to directly regulate expression of the dopamine transporter or dopamine receptor genes in humans. However , both proteins are part of the bHLH transcriptional network that drives retina development (Feng et al. 2006; Pennesi et al. 2006; Skowronska-Krawczyk et al. 2004), and the dopamine receptors are critical for normal retinal function (He et al. 2013; Nguyen-Legros et al. 1999; Ogata et al. 2012; Reis et al. 2007; Yang et al. 2013). Our own transgenic expression data show strong expression of hlh-17 in the cephalic sheath cells of wild-type animals and, on its own, do not support the direct regulation of dat-1 and dop-3 by HLH-17. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In Caenorhabditis elegans, the dopamine transporter DAT-1 regulates synaptic dopamine (DA) signaling by controlling extracellular DA levels. In dat-1(ok157) animals, DA is not taken back up presynaptically but instead reaches extrasynpatic sites where it activates the dopamine receptor DOP-3 on choligeneric motor neurons and causes animals to become paralyzed in water. This phenotype is called swimming induced paralysis (SWIP) and is dependent on dat-1 and dop-3. Upstream regulators of dat-1 and dop-3 have yet to be described in C. elegans. In our previous studies, we defined a role for HLH-17 during dopamine response through its regulation of the dopamine receptors. Here we continue our characterization of the effects of HLH-17 on dopamine signaling. Our results suggest that HLH-17 acts downstream of dopamine synthesis to regulate the expression of dop-3 and dat-1. First, we show that hlh-17 animals display a SWIP phenotype that is consistent with its regulation of dop-3 and dat-1. Second, we show that this behavior is enhanced by treatment with the dopamine reuptake inhibitor, bupropion, in both hlh-17 and dat-1 animals, a result suggesting that SWIP behavior is regulated via a mechanism that is both dependent and independent of DAT-1. Third, and finally, we show that although the SWIP phenotype of hlh-17 animals is unresponsive to the dopamine agonist, reserpine, and to the antidepressant, fluoxetine, hlh-17 animals are not defective in acetylcholine signaling. Taken together, our work suggests that HLH-17 is required to maintain normal levels of dopamine in the synaptic cleft through its regulation of dop-3 and dat-1.
    Full-text · Article · Apr 2014 · G3-Genes Genomes Genetics
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This article summarizes our recent works on stratum-by-stratum structure-function rules for synaptic contacts between retinal bipolar cells and third-order retinal neurons in the inner plexiform layer. These rules were derived from large-scale voltage clamp recordings of various types of bipolar cells in the tiger salamander retina, and they appear applicable to bipolar cells in the mouse and other mammalian species. This review also gives a brief account of how we used pathway-specific knockout mouse models to dissect rod and cone signaling channels in the mammalian retina. Furthermore, studies on cellular and genetic mechanisms underlying several neurodegenerative retinal disorders are described.
    Preview · Article · Nov 2008 · Vision research
  • [Show abstract] [Hide abstract]
    ABSTRACT: Circadian rhythms govern many aspects of mammalian physiology. The daily pattern of melatonin synthesis and secretion is one of the classic examples of circadian oscillations. It is mediated by a class of neuroendocrine cells known as pinealocytes which are not yet fully defined. An established method to evaluate functional and cytological characters is through the expression of lineage-specific transcriptional regulators. NeuroD1 is a basic helix-loop-helix transcription factor involved in the specification and maintenance of both endocrine and neuronal phenotypes. We have previously described developmental and adult regulation of NeuroD1 mRNA in the rodent pineal gland. However, the transcript levels were not influenced by elimination of sympathetic input, suggesting that any rhythmicity of NeuroD1 might be found downstream of transcription. Here we describe NeuroD1 protein expression and cellular localization in the rat pineal gland during development and the daily cycle. In embryonic and perinatal stages, protein expression follows the mRNA pattern and is predominantly nuclear. Thereafter, NeuroD1 is mostly found in pinealocyte nuclei in the early part of the night and in cytoplasm during the day, a rhythm maintained into adulthood. Additionally, nocturnal nuclear NeuroD1 levels are reduced after sympathetic disruption, an effect mimicked by the in vivo administration of α- and β-adrenoceptor blockers. NeuroD1 phosphorylation at two sites, Ser(274) and Ser(336) , associates with nuclear localization in pinealocytes. These data suggest that NeuroD1 influences pineal phenotype both during development and adulthood, in an autonomic- and phosphorylation-dependent manner. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Mar 2015 · Journal of Pineal Research