Biological clock in total darkness: The Clock / MOP3 circadian system of the blind subterranean mole rat

Self Cite

We demonstrated that a subterranean, visually blind mammal has a functional set of three Per genes that are important components of the circadian clockwork in mammals. The mole rat superspecies Spalax ehrenbergi is a blind subterranean animal that lives its entire life underground in darkness. It has degenerated eyes, but the retina and highly hypertrophic harderian gland are involved in photoperiodic perception. All three Per genes oscillate with a periodicity of 24 h in the suprachiasmatic nuclei, eye, and harderian gland and are expressed in peripheral organs. This oscillation is maintained under constant conditions. The light inducibility of sPer1 and sPer2, which are similar in structure to those of other mammals, indicates the role of these genes in clock resetting. However, sPer3 is unique in mammals and has two truncated isoforms, and its expressional analysis leaves its function unresolved. Per's expression analysis in the harderian gland suggests an important participation of this organ in the stabilization and resetting mechanism of the central pacemaker in the suprachiasmatic nuclei and in unique adaptation to life underground. L ife on Earth is adapted to cyclical phenomena imposed by the external environment (1). Most organisms have circadian systems that synchronize physiological events to the external 24-h cycle (2). The underlying molecular-genetic mechanisms of these clocks exhibit an extraordinary evolutionary conservation from cyanobacteria through plants, fruit flies, and mammals. All of these clock systems consist of autoregulatory transcriptional͞ translational feedback loops with positive͞negative regulatory elements and similar genetic machinery (3, 4).Two basic helix-loop-helix PAS (PER-ARNT-SIM) transcription factors, CLOCK and MOP3 (BMAL1), form the positive elements of the system and drive transcription of three Period (Per 1, 2, 3) and two Cryptochrome (Cry 1, 2) genes. The protein products of these genes are thought to be components of a negative feedback complex that inhibits the CLOCK͞MOP3 heterodimer, thereby closing the circadian loop.The enigma of circadian rhythms in a blind subterranean mammal is intriguing (5-7). We have already shown that a CLOCK͞MOP3-driven clock exists in Spalax (8). Here we continue to decipher its circadian machinery. The Evolutionary Model of Blind Subterranean MammalsThe blind subterranean mammals, mole rats of the Spalax ehrenbergi superspecies in Israel, consist of four species that have been studied multidisciplinarily as an evolutionary model of speciation and adaptation (5-7). Spalax lives in total darkness, yet, it perceives the daily and seasonal temporal cycles underground (9). Behaviorally, Spalax displays polyphasic and polytypic day-night activity patterns (10, 11) coupled with polymorphic (12) and seasonal ʈ variation, supported by a unique photoperiodic perception mechanism (9). Spalax has a degenerated s.c. functional eye (13,14), which, together with the harderian gland, participates in photoperiodic perception (9, 15-18). The retina h...

“…We have already shown that a CLOCK͞MOP3-driven clock exists in Spalax (8). Here we continue to decipher its circadian machinery.…”

mentioning

confidence: 80%

Section: The Evolutionary Model Of Blind Subterranean Mammalsmentioning

confidence: 99%

Circadian genes in a blind subterranean mammal II: Conservation and uniqueness of the threePeriodhomologs in the blind subterranean mole rat,Spalax ehrenbergisuperspecies

Avivi

Oster

Joel

et al. 2002

Self Cite

“…Of special interest is the high expression of heparanase in the Spalax eye (Fig. 4B, lane 6), which is atrophic and visually blind (16,17), but is assessing photoperiodicity by responding to signals that penetrate the soil and is also involved in the circadian rhythm control (40)(41)(42).…”

Section: Discussionmentioning

confidence: 99%

Adaptive evolution of heparanase in hypoxia-tolerantSpalax: Gene cloning and identification of a unique splice variant

Nasser

Nevo

Shafat

et al. 2005

Self Cite

Heparan sulfate (HS) side chains of HS proteoglycans bind to and assemble extracellular matrix proteins and play important roles in cell-cell and cell-extracellular matrix interactions. HS chains bind a multitude of bioactive molecules and thereby function in the control of multiple normal and pathological processes. Enzymatic degradation of HS by heparanase, a mammalian endoglycosidase, affects the integrity and functional state of tissues and is involved in, among other processes, inflammation, angiogenesis, and cancer metastasis. Here, we report the cloning of heparanase from four Israeli species of the blind subterranean mole rat (Spalax ehrenbergi superspecies), 85% homologous to the human enzyme. Unlike its limited expression in human tissues, heparanase is highly expressed in diverse Spalax tissues. Moreover, we have identified a unique splice variant of the Spalax enzyme lacking 16 aa encoded by exon 7. This deletion resulted in a major defect in trafficking and processing of the heparanase protein, leading to a loss of its enzymatic activity. Interspecies variation was noted in the sequence and in the expression of the splice variant of the heparanase gene in blind mole rats living under different ecogeographical stresses, indicating a possible role in adaptation to stress in Spalax evolution.alternative splicing ͉ heparan sulfate ͉ blind mole rat ͉ angiogenesis ͉ cancer H eparan sulfate (HS) proteoglycans are macromolecules associated with the cell surface and the extracellular matrix (ECM) of a wide range of cells of vertebrate and invertebrate tissues (1-3). HS binds to and assembles ECM proteins and plays important roles in the structural integrity of the ECM and in cell-cell and cell-ECM interactions. HS chains sequester a multitude of proteins and bioactive molecules and thereby function in the control of a large number of normal and pathological processes (1-4). Apart from sequestration of bioactive molecules, HS proteoglycans have a coreceptor role in which the proteoglycan, in concert with the other cell surface molecule, comprises a functional receptor complex that binds the ligand and mediates its action (3-5).Enzymatic degradation of HS by heparanase, a mammalian endoglucuronidase, affects the integrity and functional state of tissues and is involved in fundamental biological phenomena, ranging from pregnancy, morphogenesis, and development to inf lammation, angiogenesis, and cancer metastasis (6 -10). Heparanase elicits an indirect angiogenic response by releasing HS-bound angiogenic growth factors [e.g., basic fibroblast growth factor and vascular endothelial growth factor (VEGF)] from the ECM and by generating HS fragments that potentiate basic fibroblast growth factor receptor binding, dimerization, and signaling (5, 8). Despite earlier reports on the existence of several distinct mammalian HS-degrading endoglycosidases (heparanases), the cloning of the same single gene by several groups (6,7,11,12) suggests that mammalian cells express primarily a single dominant functional heparanase e...

“…For example, mole rats have degenerated, subcutaneous eyes that are visually nonfunctional, but are engaged in circadian entrainment and have increases in retinal projections to structures involved in photoperiodic and photo-neuroendocrine regulation (1-3). Moreover, the circadian rhythm transcription factor CLOCK of the blind mole rat has an expanded glutamine-rich domain that may cause a change in its transcriptional activity (33). In addition, the rhodopsin gene of Spalax is functional in retinal cells despite the overall degenerate eye (34), as is true for melanopsin and pituitary adenylate cyclase-activating peptide (PACAP) (J. Hannibal, P. Hindersson, E.N., and J. Fahrenkrug, unpublished results).…”

Section: Discussionmentioning

confidence: 99%

Adaptive evolution of small heat shock protein/ αB-crystallin promoter activity of the blind subterranean mole rat,Spalax ehrenbergi

Hough

Avivi

Davis

et al. 2002

Blind mole rats have degenerated subcutaneous eyes that are visually nonfunctional. In this investigation, we have compared the tissue specificity of the small heat shock protein (shsp)͞␣B-crystallin promoter of the mole rat superspecies, Spalax ehrenbergi, with that of the mouse. Earlier experiments showed that mouse shsp͞ ␣B-crystallin promoter͞enhancer activity is high in the lens and moderate in the heart and skeletal muscle of transgenic mice. Here, we show in transgenic mouse experiments using the firefly luciferase reporter gene that, despite relatively few changes in sequence, the mole rat shsp͞␣B-crystallin promoter͞enhancer has selectively lost lens activity after 13.5 days of embryogenesis (E13.5). The ratios of mole rat͞mouse promoter activity were 0.01 for lens, 1.7 for heart, and 13.6 for skeletal muscle in 8-wk-old transgenic mice. Our data indicate that the shsp͞␣B-crystallin promoter͞enhancer has undergone adaptive changes corresponding to the subterranean evolution of the blind mole rat. We speculate that selective pressures on metabolic economy may have contributed to these tissue-specific modifications of promoter͞ enhancer function during adaptation to life underground.