Cry1, short for Cryptochrome 1, is a core protein in the circadian clock mechanism. It participates in regulating circadian rhythms, which control ∼24-hour rhythms in many behavioral and physiological processes in humans [1,3,6]. It is also involved in regulating drug metabolism in the liver, glucose homeostasis, and may influence the racing performance of homing pigeons [2,4,5]. Genetic models, such as gene knockout mouse models, have been crucial for studying its functions.

In Cry1-null mice, hepatic CYP2A5 expression and its diurnal rhythms were reduced, along with decreased CYP2A5 activity and increased coumarin-induced hepatotoxicity, indicating that Cry1 positively regulates CYP2A5 expression and rhythms through repression of E4BP4 [2]. In diabetic mice, a reduction in hepatic Cry1 protein, stimulated by elevated E3 ligase FBXL3-dependent proteasomal degradation, contributed to excessive hepatic glucose production and hyperglycemia. GSK3β-induced Cry1 phosphorylation also potentiated this degradation [4].

In conclusion, Cry1 is essential for maintaining normal circadian rhythms, regulating drug-metabolizing enzymes in the liver, and glucose homeostasis. The study of Cry1 using gene-knockout mouse models has provided insights into its role in diabetes-related hyperglycemia, enhancing our understanding of these biological processes and potentially offering new strategies for treating related diseases.

References:

1. Patke, Alina, Murphy, Patricia J, Onat, Onur Emre, Campbell, Scott S, Young, Michael W. . Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder. In Cell, 169, 203-215.e13. doi:10.1016/j.cell.2017.03.027. https://pubmed.ncbi.nlm.nih.gov/28388406/

2. Lin, Luomin, Huang, Yuwei, Wang, Jinyi, Guo, Lianxia, Wu, Baojian. 2023. CRY1/2 regulate rhythmic CYP2A5 in mouse liver through repression of E4BP4. In Biochemical pharmacology, 217, 115843. doi:10.1016/j.bcp.2023.115843. https://pubmed.ncbi.nlm.nih.gov/37797722/

3. Cal-Kayitmazbatir, Sibel, Kulkoyluoglu-Cotul, Eylem, Growe, Jacqueline, Anafi, Ron C, Kavakli, Ibrahim Halil. 2020. CRY1-CBS binding regulates circadian clock function and metabolism. In The FEBS journal, 288, 614-639. doi:10.1111/febs.15360. https://pubmed.ncbi.nlm.nih.gov/32383312/

4. Kim, Ye Young, Jang, Hagoon, Lee, Gung, Kim, Jong-Seo, Kim, Jae Bum. . Hepatic GSK3β-Dependent CRY1 Degradation Contributes to Diabetic Hyperglycemia. In Diabetes, 71, 1373-1387. doi:10.2337/db21-0649. https://pubmed.ncbi.nlm.nih.gov/35476750/

5. Dybus, Andrzej, Kulig, Hanna, Yu, Yu-Hsiang, Proskura, Witold, Cheng, Yeong-Hsiang. 2021. CRY1 Gene Polymorphism and Racing Performance of Homing Pigeons. In Animals : an open access journal from MDPI, 11, . doi:10.3390/ani11092632. https://pubmed.ncbi.nlm.nih.gov/34573598/

6. Schirmer, Aaron E, Kumar, Vivek, Schook, Andrew, Marshall, Michael S, Takahashi, Joseph S. 2023. Cry1 expression during postnatal development is critical for the establishment of normal circadian period. In Frontiers in neuroscience, 17, 1166137. doi:10.3389/fnins.2023.1166137. https://pubmed.ncbi.nlm.nih.gov/37389366/