Timing Matters: The Role of Circadian Clock Genes In Development and Toxin Responses

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Title: Timing Matters: The Role of Circadian Clock Genes In Development and Toxin Responses
Author: Qu, Xiaoyu
Abstract: Most members of the PAS (PER -ARNT -SIM ) protein family are transcription factors , mediating development and adaptive responses to the environment , such as circadian rhythms and toxin responses . Because the PAS domain mediates protein -protein interactions and functional cross -talk between distinct biological processes , we hypothesized that PAS genes in the circadian clockworks , namely Per1 and Per2 , may be involved in development and toxin responses , which are modulated by other PAS members . To explore the possible role of clock genes in development , we examined mammary epithelial cells in vitro and the mouse mammary gland in vivo for evidences of changes in clock gene expression during different stages of development and differentiation . Our results showed that Per1 and Bmal1 expression were up -regulated in differentiated HC -11 cells , whereas Per2 mRNA levels were higher in undifferentiated cells . A similar differentiation -dependent profile of clock gene expression was observed in mouse mammary glands ; Per1 and Bmal1 mRNA levels were elevated in late pregnant and lactating mammary tissues , whereas Per2 expression was higher in proliferating virgin and early pregnant glands . These data suggest that circadian clock genes may play a role in mouse mammary gland development . To examine clock gene function in toxin responses , we evaluated whether disruption or inhibition of Per1 and /or Per2 alters toxin -induced activity of the AhR signaling pathway in the mouse mammary gland and liver . We assessed the activation of the AhR signaling pathway in response to 2 ,3 ,7 ,8 -Tetrachlorodibenzo -p -dioxin (TCDD ) , a prototypical AhR agonist , by analyzing the mRNA abundance of its two target genes , cytochrome P450 , subfamily I , polypeptide 1 (Cyp1A1 ) and Cyp1B1 . Our results showed that the targeted disruption of Per1 , but not Per2 , significantly increases the TCDD -induced p450 expression in the mammary gland and liver in vivo . Similar changes in TCDD -mediated p450 expression were observed in vitro using mammary primary cultures of mammary cells derived from from Per1ldc , Per2ldc and Per1ldc /Per2ldc mutant mice and Hepa1c1c7 cells subjected to siRNA -mediated inhibition of Per1 or Per2 . These discoveries suggest that the clock gene Per1 may modulate toxin responses perhaps by functioning as a negative regulator for TCDD -mediated activation of the AhR signaling pathway .
URI: http : / /hdl .handle .net /1969 .1 /ETD -TAMU -2886
Date: 2009-05-15

Citation

Timing Matters: The Role of Circadian Clock Genes In Development and Toxin Responses. Available electronically from http : / /hdl .handle .net /1969 .1 /ETD -TAMU -2886 .

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