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Biomedical subjects

David Morse

Publications and source records attributed to David Morse.

25 records · Page 2Linked to original sources
PubMed2003

No circadian rhythms in testis: Period1 expression is clock independent and developmentally regulated in the mouse.

Spermatogenesis is a process whereby haploid spermatozoa differentiate through meiosis from precursor stem cells. We examined the expression of circadian clock genes in the testis, to assess clock control over the timing of different developmental events. Clock genes are known to oscillate with circadian rhythmicity in the central clock structure, the suprachiasmatic nucleus of the hypothalamus, but also in peripheral tissues. Here we show that Per1 gene expression in the testis is constant over a 24-h period and that the Per1 transcript is expressed at a level higher than the peak values of the Per1 oscillations observed for other tissues. Bmal1, another clock gene whose expression oscillates in other tissues, also shows constant expression levels in the testis. In addition, the levels and phosphorylation state of the PER1 protein are not oscillating at all times of day. Strikingly, Per1 is restricted primarily to step 7 to 10 spermatids and thus appears to be developmentally regulated. The expression of the Clock transcript is also developmentally regulated, but it is found principally in spermatogonia and spermatocytes up until the time of the first meiotic division. Per1 expression is not altered in testes from Clock mutant mice, suggesting that CLOCK does not activate Per1 in male germ cells, in contrast to what it does in other mouse tissues. Taken together, our observations suggest that the testis, in contrast to all other peripheral tissues, lacks a functioning circadian clock.

ARNTL Transcription Factors↗
PubMed2003

On the communication pathways between the central pacemaker and peripheral oscillators.

Circadian rhythms are regulated by clocks located in specific structures of the CNS, such as the suprachiasmatic nucleus (SCN) in mammals, and by peripheral oscillators present in various other tissues. The expression of essential clock genes oscillates both in the SCN and in peripheral pacemakers. Peripheral tissues in the fly and in the fish are directly photoreceptive. In particular, we have established the Z3 embryonic zebrafish cell line that recapitulates the dynamic light-dependent regulation of the vertebrate clock in vitro. In mammals the synchronization to daily light cycles involves neural connections from a subset of light-sensitive receptor-containing retinal ganglion cells. Humoral and/or hormonal signals originating from the SCN are thought to provide timing cues to peripheral clocks. However, alternative routes exist, as some peripheral clocks in mammals can be specifically entrained in a SCN-independent manner by restricted feeding regimes. Thus, not all peripheral tissues are equal in circadian rhythmicity. Testis, for example, displays no intrinsic circadian rhythmicity and the molecular mechanisms of clock gene activation in male germ cells appear to differ from other tissues. The study of the connecting routes that link the SCN to peripheral tissues is likely to reveal signalling pathways of fundamental physiological significance.

Animals↗
PubMed2002

Phenotypic rescue of a peripheral clock genetic defect via SCN hierarchical dominance.

The mammalian circadian system contains both central and peripheral oscillators. To understand the communication pathways between them, we have studied the rhythmic behavior of mouse embryo fibroblasts (MEFs) surgically implanted in mice of different genotypes. MEFs from Per1(-/-) mice have a much shorter period in culture than do tissues in the intact animal. When implanted back into mice, however, the Per1(-/-) MEF take on the rhythmic characteristics of the host. A functioning clock is required for oscillations in the target tissues, as arrhythmic clock(c/c) MEFs remain arrhythmic in implants. These results demonstrate that SCN hierarchical dominance can compensate for severe intrinsic genetic defects in peripheral clocks, but cannot induce rhythmicity in clock-defective tissues.

Animals↗
PubMed2002

Time after time: inputs to and outputs from the mammalian circadian oscillators.

Oscillating levels of clock gene transcripts in the suprachiasmatic nucleus (SCN) are essential components of the mammalian circadian pacemaker. Their synchronization with daily light cycles involves neural connections from light-sensitive photoreceptor-containing retinal ganglion cells. This clock orchestrates rhythmic expression for approximately 10% of the SCN gene transcripts, of which only 10% are also rhythmically expressed in other tissues. Many of the transcripts expressed rhythmically only in the SCN are involved in neurosecretion, and their secreted products could mediate SCN control over physiological rhythms by coordinating rhythmicity in other nuclei within the brain. The coordination of clock gene transcript oscillations in peripheral tissues could be controlled directly by specific signals or indirectly by rhythmic behavior such as feeding.

Animals↗
PubMed2002

Polyadenylated transcripts containing random gene fragments are expressed in dinoflagellate mitochondria.

An AT-rich cDNA isolated from a Gonyaulax library was identified as a putative mitochondrial cytochrome oxidase subunit 3 (cox3) by sequence comparisons. Transcripts hybridizing to this cox3 probe are abundant, are found in poly(A) enriched RNA fractions and have a variable length when tested by Northern blot analysis. A PCR analysis of 21 cox3 clones, designed to measure the length of 5' and 3' ends separately, indicated that the greatest variability in length was found at the 3' end. The variable length of the 3' end may be due to polyadenylation at random sites or to a reduced stringency for polyadenylation signals. Eight cox3 cDNAs were completely sequenced, and were found to differ by up to thirteen bases in the regions of overlap. Curiously, the longest cDNA contained a 350 base pair fragment of a dinoflagellate cox1 gene and a 600 bp fragment of a cytochrome b (cob) gene in the region 3' to the cox3 sequence. Gene fragments or multiple copies of the cox3 and cob sequences may be abundant in the mitochondrial genome since Southern blots, using these sequences separately as probes, show multiple restriction fragments with several enzymes.

Amino Acid Sequence↗
PubMed1998

Bursting Dense Microspheres (Spherons) in Alzheimer's DiseaseA Review of Studies (1980-1997) on Spherons and the Pathogenesis of Alzheimer's Disease.

This paper reviews our research studies during the past 17 years on the relationship of cerebral protein dense microspheres (DMS), termed spherons, and senile plaques (SP) in the aged human brain and in AD. Initially, correlative anatomical and pathological data suggested that spherons may evolve into SP. This led to morphometric studies which strongly supported the theory. Biochemical studies were undertaken which showed that spherons could be isolated to homogeneity from brain tissue and contained the markers associated with SP. Experiments in vitro with spherons, and with inoculation of spherons into animals, reproduced SP lesion characteristics. To test the validity of using spherons for drug screening, experimental drugs were tested, a few of which are capable of blocking the formation of spheron-induced experimental SP.

Journal Article↗