Disease relevance of Arntl

• Although little pathology is observed prior to 11 weeks of age, by 35 weeks of age essentially all Mop3 null animals develop joint ankylosis due to flowing ossification of ligaments and tendons and almost complete immobilization of weight-bearing and nonweight-bearing joints [1].
• With the role of Clock and Bmal1 in fertility becoming clearer, it may be time to pursue the effect of polymorphisms in these genes in relation to the various types of infertility in humans [2].
• Here we report that Bmal1(-/-) mice have reduced lifespans and display various symptoms of premature aging including sarcopenia, cataracts, less subcutaneous fat, organ shrinkage, and others [3].
• Therefore, by a variety of criteria, we show that MOP3 has little if any role in the regulation of hypoxia responses in vivo [4].
• In the present studies, MOP3 deficient mice had significantly reduced body weight and showed remarkable mortality around six months of age [5].

Psychiatry related information on Arntl

• Additionally, locomotor activity in light-dark (LD) cycles is impaired and activity levels are reduced in Mop3-/- mice [6].
• Deletion of the mammalian circadian clock gene BMAL1/Mop3 alters baseline sleep architecture and the response to sleep deprivation [7].
• MEASUREMENTS AND RESULTS: Mice homozygous for the BMAL1/Mop3 deletion showed an attenuated rhythm of sleep and wakefulness distribution across the 24-hr period [7].

High impact information on Arntl

• Essentially, the activity of the transcription factors BMAL1 (also known as MOP3) and CLOCK is rhythmically counterbalanced by Period (PER) and Cryptochrome (CRY) proteins to govern time of day-dependent gene expression [8].
• Here, we identify the orphan nuclear receptor REV-ERBalpha as the major regulator of cyclic Bmal1 transcription [9].
• Bmal1 and Per transcription cycles display nearly opposite phases and are thus governed by different mechanisms [9].
• These results provide genetic evidence that MOP3 is the bona fide heterodimeric partner of mCLOCK [6].
• Here we show that loss of the PAS protein MOP3 (also known as BMAL1) in mice results in immediate and complete loss of circadian rhythmicity in constant darkness [6].

Chemical compound and disease context of Arntl

• The bHLH/PAS factor MOP3 does not participate in hypoxia responses [4].

Biological context of Arntl

• The aim of the study was to test whether mPer, mCry, Clock, and Bmal1 are rhythmically expressed in the mouse PT and how the absence of melatonin receptors affects clock gene expression [10].
• The transcriptional activators BMAL1/MOP3 and CLOCK drive one loop by binding to E-box motifs in the regulatory regions of circadian target genes [11].
• Molecularly, the biological clock is based on the transcriptional/translational feedback loop of clock genes (mPer, mCry, Clock, and Bmal1) [10].
• Two basic helix-loop-helix (bHLH)/PAS-containing transcription factors, CLOCK and BMAL1 (MOP3), provide the basic drive to the system by activating transcription of negative regulators through E box enhancer elements [12].
• These results indicate that RORalpha acts to promote Bmal1 transcription, thereby maintaining a robust circadian rhythm [13].

Anatomical context of Arntl

• In cultured cells, loss of endogenous RORalpha protein resulted in a dampened circadian rhythm of Bmal1 transcription, further indicating that RORalpha is a functional component of the cell-autonomous core circadian clock [13].
• Bmal1, another clock gene whose expression oscillates in other tissues, also shows constant expression levels in the testis [14].
• The expression of clock-control genes, such as Bmal1 and Rev-erbalpha, also displays diurnal oscillations in the uterus, but not in bone [15].
• This differentiation-dependent profile of clock gene expression was consistent with that observed in mouse mammary glands, as 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 [16].
• Arnt3 mRNA was expressed in brain, skeletal muscle, 13.5-day embryos, and P19 cells treated with retinoic acid [17].

Associations of Arntl with chemical compounds

• We demonstrate a role for Bmal1 and Clock in the regulation of glucose homeostasis [18].
• Here we show that the retinoic acid receptor-related orphan receptor RORalpha (NR1F1) directly activates transcription of Bmal1 through two conserved RORalpha response elements that are required for cell-autonomous transcriptional oscillation of Bmal1 mRNA [13].
• Lithium treatment of cells leads to rapid proteasomal degradation of Rev-erbalpha and activation of clock gene Bmal1 [19].
• The vasopressin gene is expressed in the suprachiasmatic nucleus where the basic helix-loop-helix (bHLH)-PAS factors CLOCK and MOP3 regulate circadian expression through interactions with E-box sequences [20].

Regulatory relationships of Arntl

• Here we show that Rev-erbalpha dramatically represses the basal activity of the mouse Bmal1 gene promoter via two monomeric binding sites, both of which are required for repression and are conserved between mouse and human [21].

Other interactions of Arntl

• Clock and Bmal1 are essential transcription factors that drive the expression of three period genes (Per1-3) and two cryptochrome genes (Cry1 and Cry2) [22].
• Positive involvement of RORalpha in generation of the Bmal1 circadian oscillation was verified by behavioral analyses of RORalpha-deficient staggerer mice that showed aberrant locomotor activity and unstable rhythmicity [13].
• We found that expression of Bmal1 and Cry1 was higher at 1300 h, or zeitgeber time 6, whereas expression of Per1 was higher at 0100 h (zeitgeber time 18) [23].
• The phase of Per2 and Bmal1 expression remained unchanged regardless of feeding condition [24].
• Brain and muscle Arnt-like protein-1 (BMAL1; also known as MOP3 or Arnt3) is a transcription factor known to regulate circadian rhythm [25].

Analytical, diagnostic and therapeutic context of Arntl

• DESIGN: In mice with targeted deletion of the BMAL1/Mop3 gene, EEG/EMG sleep-wake patterns were recorded under entrained and free-running conditions as well as following acute (6-hrs) sleep deprivation [7].
• However, gel-shift analysis shows that the cooperative effect of HIF-1alpha and CLOCK results in MOP3 binding, but does not involve heterodimerization of HIF-1alpha/CLOCK, at E-box A [20].
• Flow cytometry analysis showed the levels of pre-B cells in bone marrow of MOP3(-/-) mice were similar as that in control mice [26].
• Adoptive transfer of MOP3(-/-) bone marrow cells (BMC) to lethally irradiated BALB/c Rag2(-/-) recipients, normal T and B cell development was observed, whereas Adoptive transfer of BALB/c BMC to lethally irradiated MOP3(-/-) recipients, B-cell development was significantly impaired [26].

References