Splicing the clock is timeless : from fruit fly behavior to mammalian retinal degeneration / Iryna Shakhmantsir.

Format:

Book

Manuscript

Thesis/Dissertation

Author/Creator:

Shakhmantsir, Iryna, author.

Contributor:

Sehgal, Amita, degree supervisor.

Bashaw, Greg J., degree committee member.

Jongens, Thomas A., degree committee member.

Raizen, David M., degree committee member.

FitzGerald, G. A. (Garret A.), degree committee member.

University of Pennsylvania. Department of Cell and Molecular Biology, degree granting institution.

Language:

English

Subjects (All):

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Local Subjects:

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Physical Description:

vii, 103 leaves : illustrations (chiefly color) ; 29 cm

Production:

[Philadelphia, Pennsylvania] : University of Pennsylvania, 2019.

Summary:

Circadian rhythms synchronize intrinsic cycles of physiology and behavior with diurnal environmental oscillations of light and temperature. Circadian transcription-translation feedback loops (TTFLs), in which the rhythmic expression of core clock proteins negatively regulates their own expression, are a central mechanism of all eukaryotic circadian clocks. How TTFLs maintain separate phases of transcription and negative feedback and generate a ~24 hour period is a key unresolved question in the field. In this thesis, we uncover a novel splicing factor-mediated mechanism that sets the pace of the clock in both fruit flies and mice. In a Drosophila screen for novel clock regulators, we identify pre-mRNA splicing kinase 4 (prp4) and show its requirement for establishing a delay between transcriptional activation and repression in the TTFL. One of the clock-relevant targets of PRP4 is a retained intron in tim (that we call tim-tiny). We characterize a mechanism by which a splice choice at tim-tiny affects TIM accumulation to set the timing of the clock in constant dark and under temperature cycles. In addition to PRP4, we identify a circadian function for multiple components of U4/U5.U6 triple small nuclear ribonucleoprotein (tri-snRNP), and propose a conserved circadian role for these splicing factors. Our studies in the mouse model of retinitis pigmentosa (RP) support this hypothesis and demonstrate that a Prpf8 knockin mutation lengthens circadian wheel-running behavior and dampens the diurnal rhythm in select transcripts of the mouse retina. We explore the relevance of these findings in the context of RP pathology, in particular asking whether clock disruption could contribute to retinal degeneration.

Notes:

Ph. D. University of Pennsylvania 2019.

Department: Cell and Molecular Biology.

Supervisor: Amita Sehgal.

Includes bibliographical references.

Other Format:

Online version: Shakhmantsir, Iryna. Splicing the clock is timeless.

OCLC:

1129588864