Pineal Regulation: Molecular basis of development

松果体调节：发育的分子基础

• 批准号: 8941521
• 负责人: David Klein
• 金额: $ 0.52万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8941521
• 关键词: Acetyl Coenzyme A; Acetylation; Acetyltransferase; Adult; Affect; Age-Months; Anterior; BHLH Protein; Binding; Biological; Brain; Catalysis; Cells; Chronobiology Disorders; Cre-LoxP; Development; Disease; Electroretinography; Elements; Embryo; Endocrine; Enzymes; Event; Evolution; Exhibits; Eye Development; Fishes; Gene Chips; Gene Duplication; Gene Expression; Gene Expression Profile; Genes; Genetic Recombination; Genome; Goals; Histologic; Homeobox; Homeostasis; Knock-out; Knockout Mice; Learning; Light; Maintenance; Melatonin; Microarray Analysis; Modeling; Molecular; Molecular Evolution; Monitor; Mutate; Neural Fold; Pattern; Phenethylamines; Phenotype; Photoreceptors; Physiological; Pineal gland; Pinealocyte; Play; Positioning Attribute; Process; Production; Proteins; Psyche structure; Quantitative Reverse Transcriptase PCR; RNA Interference; Rattus; Regulation; Regulatory Element; Research; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Retinal Photoreceptors; Role; Sea Bream; Serotonin; Sleep; Specificity; Structure; Structure-Activity Relationship; Substrate Specificity; Testing; Tissues; Transcript; Undifferentiated; Vertebrate Photoreceptors; Vertebrates; Work; base; duplicate genes; immune function; interest; neurodevelopment; paralogous gene; postnatal; preference; prevent; promoter; recombinase; selective expression; teleost fish; three-dimensional modeling; transcription factor

Rax: Retina and anterior neural fold homeobox (Rax) gene encodes a transcription factor essential for vertebrate eye development. Recent microarray studies indicate that Rax is expressed in the adult rat pineal gland and retina. The present study reveals that Rax expression levels in the rat change significantly during retinal development with a peak occurring at embryonic day 18, whereas Rax expression in the pineal is relatively delayed and not detectable until embryonic day 20. In both tissues, Rax is expressed throughout postnatal development into adulthood. In the mature rat pineal gland, the abundance of Rax transcripts increases 2-fold during the light period with a peak occurring at dusk. These findings are consistent with the evidence that Rax is of functional importance in eye development and suggest a role of Rax in the developing pineal gland. In addition, it would appear possible that Rax contributes to phenotype maintenance in the mature retina and pineal gland and may facilitate 24-h changes in the pineal transcriptome.(From Rhode et al., 2011). NeuroD: NeuroD1 encodes a basic helix-loop-helix transcription factor involved in the development of neural and endocrine structures, including the retina and pineal gland. To determine the effect of NeuroD1 knockout in these tissues, a Cre/loxP recombination strategy was used to target a NeuroD1 floxed gene and generate NeuroD1 conditional knockout (cKO) mice. Tissue specificity was conferred using Cre recombinase expressed under the control of the promoter of Crx, which is selectively expressed in the pineal gland and retina. At 2 months of age, NeuroD1 cKO retinas have a dramatic reduction in rod- and cone-driven electroretinograms and contain shortened and disorganized outer segments; by 4 months, NeuroD1 cKO retinas are devoid of photoreceptors. In contrast, the NeuroD1 cKO pineal gland appears histologically normal. Microarray analysis of 2-month-old NeuroD1 cKO retina and pineal gland identified a subset of genes that were affected 2-100-fold; in addition, a small group of genes exhibit altered differential night/day expression. Included in the down-regulated genes are Aipl1, which is necessary to prevent retinal degeneration, and Ankrd33, whose protein product is selectively expressed in the outer segments. These findings suggest that NeuroD1 may act through Aipl1 and other genes to maintain photoreceptor homeostasis. Molecular Evolution: ArylalkylamineN-acetyltransferase (AANAT) catalyzes the transfer of an acetyl group from acetyl coenzyme A (AcCoA) to arylalkylamines, including indolethylamines and phenylethylamines. Multiple aanats are present in teleost fish as a result of whole genome and gene duplications. Fish aanat1a and aanat2 paralogs display different patterns of tissue expression and encode proteins with different substrate preference: AANAT1a is expressed in the retina, and acetylates both indolethylamines and phenylethylamines; while AANAT2 is expressed in the pineal gland, and preferentially acetylates indolethylamines. The two enzymes are therefore thought to serve different roles. Here, the molecular changes that led to their specialization were studied by investigating the structure-function relationships of AANATs in the gilthead seabream (sb, Sperus aurata). Acetylation activity of reciprocal mutated enzymes pointed to specific residues that contribute to substrate specificity of the enzymes. Inhibition tests followed by complementary analyses of the predicted three-dimensional models of the enzymes, suggested that both phenylethylamines and indolethylamines bind to the catalytic pocket of both enzymes. These results suggest that substrate selectivity of AANAT1a and AANAT2 is determined by the positioning of the substrate within the catalytic pocket, and its accessibility to catalysis. This illustrates the evolutionary process by which enzymes encoded by duplicated genes acquire different activities and play different biological roles. (From Zilberman-Peled et al., 2011).

视网膜和前神经折叠同源盒（Rax）基因编码脊椎动物眼睛发育所必需的转录因子。最近的微阵列研究表明Rax在成年大鼠松果体和视网膜中表达。本研究表明，Rax在大鼠视网膜发育过程中的表达水平发生显著变化，在胚胎第18天达到峰值，而Rax在松果体中的表达相对延迟，直到胚胎第20天才可检测到。在这两种组织中，Rax的表达贯穿于出生后到成年的整个发育过程。在成熟大鼠松果体中，Rax转录本的丰度在光照期增加2倍，黄昏时达到峰值。这些发现与Rax在眼睛发育中具有重要功能的证据一致，并表明Rax在松果体发育中起作用。此外，Rax似乎可能有助于成熟视网膜和松果体的表型维持，并可能促进松果体转录组的24小时变化。（摘自罗德等人，2011）。