The organization of biological activities into daily cycles is universal in organisms as diverse as cyanobacteria, fungi, algae, plants, flies, birds and man. Comparisons of circadian clocks in unicellular and multicellular organisms using molecular genetics and genomics have provided new insights into the mechanisms and complexity of clock systems. Whereas unicellular organisms require stand-alone clocks that can generate 24-hour rhythms for diverse processes, organisms with differentiated tissues can partition clock function to generate and coordinate different rhythms. In both cases, the temporal coordination of a multi-oscillator system is essential for producing robust circadian rhythms of gene expression and biological activity.The temporal coordination of internal biological processes, both among these processes and with external environmental cycles, is crucial to the health and survival of diverse organisms, from bacteria to humans. Central to this coordination is an internal CLOCK that controls CIRCADIAN RHYTHMS of gene expression and the resulting biological activity (BOX 1). Despite disparate phylogenetic origins and vast differences in complexity among the species that show circadian rhythmicity, at the core of all circadian clocks is at least one internal autonomous circadian OSCILLATOR. These oscillators contain positive and negative elements that form autoregulatory feedback loops, and in many cases these loops are used to generate 24-hour timing circuits 1, 2 . Components of these loops can directly or indirectly receive environmental input to allow ENTRAINMENT of the clock to environmental time and transfer temporal information through output Competing interests statementThe authors declare no competing financial interests. NIH Public Access Author ManuscriptNat Rev Genet. Author manuscript; available in PMC 2009 September 1. Published in final edited form as:Nat Rev Genet. 2005 July ; 6(7): 544-556. doi:10.1038/nrg1633. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript pathways to regulate rhythmic clock-controlled gene (CCG) expression and rhythmic biological activity.Whereas a self-contained clock in single-celled organisms programmes 24-hour rhythms in diverse processes, multicellular organisms with differentiated tissues can partition clock function among different cell types to coordinate tissue-specific rhythms and maintain precision. Now that individual molecular circadian oscillators have been sufficiently described, it has become possible to go beyond single oscillators to try and understand how multiple oscillators are integrated into circadian systems. Evidence accumulated in recent years indicates that the intracellular oscillator systems of single-celled organisms might be more complex than those of higher eukaryotes, whereas the complexity of circadian outputs in multicellular organisms is an emergent property of intercellular interactions. In this review, we discuss the complexity of the circadian clocks on the basis of molecular genetic and geno...

LEA proteins are late embryogenesis abundant in the seeds of many higher plants and are probably universal in occurrence in plant seeds. LEA mRNAs and proteins can be induced to appear at other stages in the plant's life by desiccation stress and/or treatment with the plant hormone abscisic acid (ABA). A role in protecting plant structures during water loss is likely for these proteins, with ABA functioning in the stress transduction process. Presented here are conserved tracts of amino acid sequence among LEA proteins from several species that may represent domains functionally important in desiccation protection. Curiously, an 11 amino acid sequence motif is found tandemly repeated in a group of LEA proteins of vastly different sizes. Analysis of this motif suggests that it exists as an amphiphilic α helix which may serve as the basis for higher order structure.

The risk of cancer was ascertained in 136 women with sicca syndrome followed at the National Institutes of Health (NIH). Seven patients developed non-Hodgkin's lymphoma from 6 months to 13 years after their first admission to NIH. This was 43.8 times (P less than 0.01) the incidence expected from the rates of cancer prevailing among women of the same age range in the general population during this time. In addition, three cases of Waldenström's macroglobulinemia occurred in this study group. Eight patients developed cancers other than lymphoma, similar to the number expected based on the rates prevailing in the general population. Patients with a history of parotid enlargement, splenomegaly, and lymphadenopahy had an increased risk of lymphoma. These clinical conditions did not appear to be early manifestations of undiagnosed lymphoma but rather seemed to identify a subgroup of patients with sicca syndrome with marked lymphoid reactivity, who had a particularly high risk of subsequently developing lymphoma.

Light signaling pathways and circadian clocks are inextricably linked and have profound effects on behavior in most organisms. Here, we used chromatin immunoprecipitation (ChIP) sequencing to uncover direct targets of the Neurospora crassa circadian regulator White Collar Complex (WCC). The WCC is a blue-light receptor and the key transcription factor of the circadian oscillator. It controls a transcriptional network that regulates ϳ20% of all genes, generating daily rhythms and responses to light. We found that in response to light, WCC binds to hundreds of genomic regions, including the promoters of previously identified clock-and lightregulated genes. We show that WCC directly controls the expression of 24 transcription factor genes, including the clock-controlled adv-1 gene, which controls a circadian output pathway required for daily rhythms in development. Our findings provide links between the key circadian activator and effectors in downstream regulatory pathways.

Understanding gene regulatory networks (GRNs) that control neuronal differentiation will provide systems-level perspectives on neurogenesis. We have previously constructed a model for a GRN in retinal ganglion cell (RGC) differentiation in which four hierarchical tiers of transcription factors ultimately control the expression of downstream terminal genes. Math5 occupies a central node in the hierarchy because it is essential for the formation of RGCs and the expression of the immediate downstream factor Pou4f2. Based on its expression, we also proposed that Isl1, a LIM-homeodomain factor, functions in parallel with Pou4f2 and downstream of Math5 in the RGC GRN. To determine whether this was the case, a conditional Isl1 allele was generated and deleted specifically in the developing retina. Although RGCs formed in Isl1-deleted retinas, most underwent apoptosis, and few remained at later stages. By microarray analysis, we identified a distinct set of genes whose expression depended on Isl1. These genes are all downstream of Math5, and some of them, but not all, also depend on Pou4f2. Additionally, Isl1 was required for the sustained expression of Pou4f2, suggesting that Isl1 positively regulates Pou4f2 after Math5 levels are diminished. The results demonstrate an essential role for Isl1 in RGC development and reveal two distinct but intersecting branches of the RGC GRN downstream of Math5, one directed by Pou4f2 and the other by Isl1. They also reveal that identical RGC expression patterns are achieved by different combinations of divergent inputs from upstream transcription factors.cell differentiation ͉ gene regulatory network ͉ transcription factors ͉ retinogenesis R etinal development is especially attractive for gene regulatory network (GRN) analysis because it represents a relatively simple, highly amenable sensory tissue with a small number of neuronal cell types connected to visual centers in the brain by the optic nerve (1, 2). A canonical GRN has been proposed for retinal determination genes in insects and mammals that is composed of seven to eight highly conserved transcription factors (3). In the mouse, one of the retinal determination factors, the pair-rule homeobox factor Pax6, is essential for the formation of all retinal cell types with the exception of amacrine cells (4). Pax6 is required in retinal progenitor cells (RPCs) for the expression of several critical transcription factors that then control the development of individual retinal cell types. One of these factors is Math5, a proneural basic helix-loop-helix factor that is essential for specifying retinal ganglion cells (RGCs) (5, 6), the first cells to differentiate in the developing retina. Pax6-Math5-expressing RPCs define a competence field that permits the subsequent steps of RGC formation to proceed (7,8). Based on these facts, we have constructed a GRN model for RGC development that features a downward cascade of transcription factors occupying distinct hierarchical tiers (8).In the RGC GRN, Math5 activates genes that encode immediat...

Exposure to radioactive iodine was strongly associated with increased risk of thyroid cancer among those exposed as children and adolescents. In the absence of Chornobyl radiation, 11.2 thyroid cancer cases would have been expected compared with the 45 observed, i.e., a reduction of 75% (95% CI = 50% to 93%). The study also provides quantitative risk estimates minimally confounded by any screening effects. Caution should be exercised in generalizing these results to any future similar accidents because of the potential differences in the nature of the radioactive iodines involved, the duration and temporal patterns of exposures, and the susceptibility of the exposed population.

The catalase multigene family in Arabidopsis includes three genes encoding individual subunits that associate to form at least six isozymes that are readily resolved by nondenaturing gel electrophoresis. CATl and CAT3map to chromosome 1 , and CAT2maps to chromosome 4. The nucleotide sequences of the three coding regions are 70 to 72% identical. The amino acid sequences of the three catalase subunits are 75 to 84% identical and 87 to 94% similar, considering conservative substitutions. Both the individual isozymes and the individual subunit mRNAs show distinct patterns of spatial (organ-specific) expression. Six isozymes are detected in flowers and leaves and two are seen in roots. Similarly, mRNA abundance of the three genes varies among organs. All three mRNAs are highly expressed in bolts, and CAT2 and CAT3 are highly expressed in leaves.

Abscisic acid-responsive gene expression is regulated by numerous transcription factors, including a subgroup of basic leucine zipper factors that bind to the conserved cis-acting sequences known as ABA-responsive elements. Although one of these factors, ABA-insensitive 5 (ABI5), was identified genetically, the paucity of genetic data for the other family members has left it unclear whether they perform unique functions or act redundantly to ABI5 or each other. To test for potential redundancy with ABI5, we identified the family members with most similar effects and interactions in transient expression systems (ABF3 and ABF1), then characterized loss-of-function lines for those loci. The abf1 and abf3 monogenic mutant lines had at most minimal effects on germination or seed-specific gene expression, but the enhanced ABA- and stress-resistance of abf3 abi5 double mutants revealed redundant action of these genes in multiple stress responses of seeds and seedlings. Although ABI5, ABF3, and ABF1 have some overlapping effects, they appear to antagonistically regulate each other's expression at specific stages. Consequently, loss of any one factor may be partially compensated by increased expression of other family members.