Arntl
Mus musculus
Gene Name: basic helix-loop-helix ARNT like 1
Aliases: Arnt3, BMAL1b, Bmal1, MOP3, bHLHe5, bmal1b'
Human Ortholog: ARNTL
Aliases: Arnt3, BMAL1b, Bmal1, MOP3, bHLHe5, bmal1b'
Human Ortholog: ARNTL
Summary Statistics:
# of Reports: 2
# of Models: 4
# of Reports: 2
# of Models: 4
External Links
Model Summary
Reduced Bmal1 expression results in decreased levels of clock proteins, including Per1, Per2, Cry 1, and Clock but increased mTOR activities in the brain Bmal1 knockout mice exhibited aberrant ultrasonic vocalizations during maternal separation, deficits in sociability and social novelty, excessive repetitive behaviors, impairments in motor coordination, as well as increased anxiety-like behavior. The novel object recognition memory remained intact.
References
Type
Title
Author, Year
Primary
Autistic-like behavior and cerebellar dysfunction in Bmal1 mutant mice ameliorated by mTORC1 inhibition
Additional
Haploinsufficiency of a Circadian Clock Gene Bmal1 ( Arntl or Mop3) Causes Brain-Wide mTOR Hyperactivation and Autism-like Behavioral Phenotypes in Mice
M_BMAL1_2_KO_HT
Model Type:
Genetic
Model Genotype: Heterozygous
Mutation: The helix-loop-helix domain within exon 4 and all of exon 5 were replaced with a neomycin resistance gene cassette.
Allele Type: Knockout
Strain of Origin: 129/Sv
Genetic Background: C57BL/6J
ES Cell Line: GS1
Mutant ES Cell Line:
Model Source: Jackson Laboratory
Model Genotype: Heterozygous
Mutation: The helix-loop-helix domain within exon 4 and all of exon 5 were replaced with a neomycin resistance gene cassette.
Allele Type: Knockout
Strain of Origin: 129/Sv
Genetic Background: C57BL/6J
ES Cell Line: GS1
Mutant ES Cell Line:
Model Source: Jackson Laboratory
M_BMAL1_3_CKO_HM
Model Type:
Genetic
Model Genotype: Homozygous
Mutation: Conditional knockout mice have Bmal1 specifically deleted in cerebellar Purkinje cells, by expressing Cre transgene inserted into exon 4 of a Pcp2 gene (L7-Cre)
Allele Type: Conditional Knockout
Strain of Origin: 129S4/SvJae; (129X1/SvJ x 129S1/Sv)F1-Kitl+
Genetic Background: C57BL/6J
ES Cell Line: J1; R1
Mutant ES Cell Line:
Model Source: Jackson Laboratory
Model Genotype: Homozygous
Mutation: Conditional knockout mice have Bmal1 specifically deleted in cerebellar Purkinje cells, by expressing Cre transgene inserted into exon 4 of a Pcp2 gene (L7-Cre)
Allele Type: Conditional Knockout
Strain of Origin: 129S4/SvJae; (129X1/SvJ x 129S1/Sv)F1-Kitl+
Genetic Background: C57BL/6J
ES Cell Line: J1; R1
Mutant ES Cell Line:
Model Source: Jackson Laboratory
M_BMAL1_1_KO_HM
Model Type:
Genetic
Model Genotype: Homozygous
Mutation: The helix-loop-helix domain within exon 4 and all of exon 5 were replaced with a neomycin resistance gene cassette.
Allele Type: Knockout
Strain of Origin: 129/Sv
Genetic Background: C57BL/6J
ES Cell Line: GS1
Mutant ES Cell Line:
Model Source: Jackson Laboratory
Model Genotype: Homozygous
Mutation: The helix-loop-helix domain within exon 4 and all of exon 5 were replaced with a neomycin resistance gene cassette.
Allele Type: Knockout
Strain of Origin: 129/Sv
Genetic Background: C57BL/6J
ES Cell Line: GS1
Mutant ES Cell Line:
Model Source: Jackson Laboratory
M_BMAL1_2_KO_HT
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Circadian rhythm: Protein expression periodicity2
Abnormal
Description: There was differential expression of multiple clock genes, including Per1, Nr1d1, Npas2, Rps27a, and Aldh1a3.
Quantitative PCR (qRT-PCR)
6-8 weeks
Circadian rhythm: protein expression periodicity1
Decreased
Description: The levels of clock proteins, including Per1, Per2 Clock, and Cry 1, were decreased by ~50% in the forebrains of Bmal1 heterozygous mutant mice.
Western blot
unreported
Circadian rhythm: Protein expression periodicity2
Abnormal
Description: There was differential expression of multiple clock genes, including Per1, Per2, Per3, Clock, Npas2, and Nr1d1.
RNA sequencing
6-8 weeks
Circadian rhythm: Protein expression periodicity2
Decreased
Description: There was differential expression of multiple clock genes, including PER1, PER2, and NR1D1.
Western blot
6-8 weeks
Motor coordination and balance2
Decreased
Description: Bmal1 knockout mice displayed markedly shorter latencies to fall and fell at slower rotating speeds compared with the wildtype mice. In contrast to the wildtype mice, the knockout performance was not improved by training.
Accelerating rotarod test
6-8 weeks
Gait2
Decreased
Description: The stride length of Bmal1 knockout mice was decreased but the bases of support were not changed as compared to the wildtype mice.
Footprint analysis
6-8 weeks
General locomotor activity: Ambulatory activity2
Increased
Description: Bmal1 knockout mice traveled a longer distance compared with the wildtype mice.
Open field test
6-8 weeks
Motor learning2
Decreased
Description: Bmal1 knockout mice needed significantly more pre-training trials than the wildtype mice to reach criterion.
Accelerating rotarod test
6-8 weeks
General locomotor activity: ambulatory activity1
Increased
Description: Bmal1 heterozygous mutant mice traveled a longer distance in the outside zone and a longer total distance compared to wildtype mice.
Open field test
6-8 weeks
Motor coordination and balance1
Decreased
Description: There was no difference in the numbers of pretraining trials between Bmal1 heterozygous mutant mice and wildtype mice. Further, the motor performance was significantly improved in both wildtype and Bmal1 heterozygous mutant mice over eight trials. However, Bmal1 heterozygous mutant mice showed a significantly lower latency to fall and fell at significantly slower rotating speeds in Trials 1, 6, 7, and 8 compared to wildtype mice.
Accelerating rotarod test
6-8 weeks
General locomotor activity2
Increased
Description: Knockout mice also exhibited a greater number of overall entries compared with the wildtype mice.
Three-chamber social approach test
6-8 weeks
Neuronal number: Purkinje cells2
Increased
Description: There was a significant increase of Purkinje cell density in the cerebellum of Bmal1 knockout mice compared with the wildtype mice.
Exp Paradigm: Calbindin-D
Exp Paradigm: Calbindin-D
Immunostaining
6-8 weeks
Cortical thickness2
Decreased
Description: There was no difference in the thickness of the molecular layer of Bmal1 knockout mice, but a moderate decrease in the thickness of the granular layer compared with the wildtype mice.
Exp Paradigm: Hematoxylin and eosin staining
Exp Paradigm: Hematoxylin and eosin staining
Immunohistochemistry
6-8 weeks
Neuronal number: interneurons2
Decreased
Description: There was a significant decrease of cerebellar interneurons in the molecular layer of the Bmal1 knockout mice, but no difference in the number of cerebellar granule cells between wildtype and Bmal1 knockout mice.
Exp Paradigm: Fox2, NeuN
Exp Paradigm: Fox2, NeuN
Immunostaining
6-8 weeks
Dendritic architecture: spine morphology2
Abnormal
Description: The fraction of immature dendritic spines (filopodial or branched) was increased, whereas the fraction of mature dendritic spines (stubby or mushroom shaped) was decreased in the Purkinje cells of Bmal1 knockout mice.
Golgi-Cox staining
6-8 weeks
Neuronal size2
Increased
Description: There was a significant increase of Purkinje cell soma length in the cerebellum of Bmal1 knockout mice compared with the wildtype mice.
Exp Paradigm: Calbindin-D
Exp Paradigm: Calbindin-D
Immunostaining
6-8 weeks
Dendritic architecture: spine density2
Increased
Description: The density of dendritic spines in the Purkinje cells was increased in the Bmal1 knockout mice compared with the wildtype mice.
Golgi-Cox staining
6-8 weeks
Action potential property: firing rate2
Decreased
Description: Bmal1 knockout mice show a remarkable reduction (~40%) of spontaneous firing rates in the Purkinje cells compared with wildtype mice. When both excitatory and inhibitory transmission were blocked, the spontaneous firing rates were not significantly affected by the blockers and the rate was also markedly reduced (~30%) in the knockout mice compared with the wildtype mice.
Whole-cell patch clamp
6-8 weeks
Action potential property: firing pattern2
Abnormal
Description: Histograms of interspike interval reveal a more spread distribution in knockout mice compared with that in wildtype mice.
Whole-cell patch clamp
6-8 weeks
Spontaneous post synaptic event amplitude: inhibitory currents2
Increased
Description: Inhibitory postsynaptic currents (IPSCs) elicited by parallel fiber stimulation gradually increased in response to increasing stimulus intensity in wildtype and knockout mice. The amplitude of IPSCs was about two-fold higher in the Bmal1 knockout mice compared with the wildtype mice.
Whole-cell patch clamp
6-8 weeks
Spontaneous post synaptic event amplitude: excitatory currents2
Increased
Description: For excitatory postsynaptic currents (EPSCs) elicited by parallel fiber stimulation, there was a two-fold increase in EPSC amplitudes in Bmal1 knockout mice compared with the wildtype mice. For EPSCs elicited by climbing fiber stimulation, there was a three-fold increase in EPSC amplitudes in Bmal1 knockout mice compared with the wildtype mice.
Exp Paradigm: Parallel fiber stimulation; Climbing fiber stimulation
Exp Paradigm: Parallel fiber stimulation; Climbing fiber stimulation
Whole-cell patch clamp
6-8 weeks
Self grooming2
Increased
Description: Water puff-induced grooming was also increased significantly in Bmal1 knockout mice compared with the wildtype mice.
Splash test to evoke grooming behavior
6-8 weeks
Repetitive digging2
Decreased
Description: Bmal1 knockout mice displayed markedly reduced activities in marble-burying and nestlet shredding tests compared with the wildtype mice.
Marble-burying test
6-8 weeks
Self grooming1
Increased
Description: Both grooming bouts and grooming time were significantly increased in the Bmal1 heterozygous mutant mice compared with wildtype mice.
Splash test to evoke grooming behavior
6-8 weeks
Repetitive digging1
Increased
Description: Bmal1 heterozygous mutant mice buried a larger number of marbles compared to wildtype mice.
Marble-burying test
6-8 weeks
Self grooming2
Increased
Description: Bmal1 knockout mice exhibited a significantly increased number of spontaneous grooming bouts, but there was no difference in overall time spent grooming.
Grooming behavior assessments
6-8 weeks
Stereotypy2
Increased
Description: The number of bouts and duration of route tracing, as well as the percentage of time spent route tracing were increased in the knockout mice compared with the wildtype mice.
Ambulation recordings
6-8 weeks
Self grooming1
Increased
Description: Bmal1 heterozygous mutant mice exhibited more bouts of spontaneous grooming, but similar total grooming time compared to wildtype mice.
Grooming behavior assessments
6-8 weeks
Social scent marking or recognition2
Decreased
Description: Bmal1 knockout mice exhibited markedly reduced preference towards the social odor (cage swab).
Olfactory habituation-dishabituation test
6-8 weeks
Social approach1
Decreased
Description: Bmal1 heterozygous mutant mice spent similar time in the chamber containing the stranger mouse as the chamber containing the empty cage, and similar times sniffing the both cages, whereas wildtype spent a longer time in the chamber containing the stranger mouse than the empty cage chamber. No difference was detected in the number of entries to the stranger mouse and the empty cage chambers in either the wildtype or Bmal1 heterozygous mice.
Three-chamber social approach test
6-8 weeks
Social memory1
Decreased
Description: Bmal1 heterozygous mutant mice spent significantly more time in the chamber containing the familiar mouse than in the chamber containing the novel mouse, and a similar time sniffing in both cages. No difference was detected in the number of entries to the familiar mouse and the novel mouse chambers in either the wildtype or Bmal1 heterozygous mice.
Three-chamber social approach test
6-8 weeks
Nest building behavior2
Decreased
Description: Bmal1 knockout mice displayed markedly reduced activities nestlet shredding tests compared with the wildtype mice.
Nest building assay
6-8 weeks
Social interaction2
Decreased
Description: Bmal1 knockout mice spent less time engaging in social interactions including anogenital sniffing, push-crawl, and following, compared with the wildtype mice. However, the time spent nose-nose sniffing was not different between the wildtype and the knockout mice.
Reciprocal social interaction test
6-8 weeks
Social approach2
Decreased
Description: Bmal1 knockout mice spent similar time in both the empty chamber and the chamber containing the stranger mouse and in sniffing the two cages.
Three-chamber social approach test
6-8 weeks
Ultrasonic vocalization: Isolation induced1
Increased
Description: Wildtype mice exhibited a trend of decreasing in the number of calls, developing from P7 to P14, but no such trend was found in the Bmal1 heterozygous mutant mice; The number of calls was increased in both the Bmal1 mutant pups as compared to the wildtype mice at P14; Bmal1 heterozygous mutant mice exhibited a longer call duration compared to wildtype pups at P7.
Monitoring ultrasonic vocalizations
P7, P14
Depression2
Decreased
Description: Bmal1 knockout mice exhibited shorter immobility time in the forced swim test.
Forced swim test
6-8 weeks
Depression2
Decreased
Description: Bmal1 knockout mice exhibited decreased latency to feed in the novelty suppressed feeding test.
Novelty-suppressed feeding paradigm
6-8 weeks
Anxiety2
Increased
Description: Bmal1 knockout mice spent less time in the center and more time in the corner zones compared with the wildtype mice.
Open field test
6-8 weeks
Anxiety1
Increased
Description: Bmal1 heterozygous mutant mice spent less time in the center zone, but more time in the outside zone during the open field test compared to wildtype mice.
Open field test
6-8 weeks
Targeted expression2
Decreased
Description: Bmal1 was eliminated in Bmal1 knockout cerebellum.
Western blot
6-8 weeks
Signaling: mTOR pathway2
Increased
Description: Hyperactivation of the mTORC1/S6K1 pathway was detected, as demonstrated by increased levels of phospho-S6K1(Thr389) and phospho-S6 (Ser240/244).
Western blot
6-8 weeks
Gene expression2
Abnormal
Description: There was differential expression of multiple genes, including Ntng2, Mfrp, Nr4a2, Ntng1, Thbs1, Atxn3, Atxn7.
Quantitative PCR (qRT-PCR)
6-8 weeks
Signaling: mTOR pathway1
Increased
Description: p-S6 levels were increased by ~50% in the cerebellum and the forebrain of Bmal1 heterozygous mutant mice compared to the levels in the wildtype mice; The levels of p-mTOR and p-S6K1, but not the level of p-4E-BP, were increased by about 50% in the forebrain of Bmal1 heterozygous mutant mice.
Western blot
unreported
Regulation of translation2
Abnormal
Description: Moderate but significant increases of phosphorylation of eIF2α and eIF4E were also detected.
Western blot
6-8 weeks
Targeted expression1
Decreased
Description: The level of Bmal1 was decreased by ~50% in the cerebellum and ~75% in the forebrain of the Bmal1 heterozygous mutant mice compared to wildtype mice.
Western blot
unreported
Differential gene expression: ASD risk genes2
Abnormal
Description: There was 7 upregulated and 12 downregulated genes included in the SFARI autism gene database.
RNA sequencing
6-8 weeks
Signaling: mTOR pathway1
Increased
Description: p-S6 labeling was colocalized with Calbindin-D (28k) labeling, indicating that mTORC1 activities are enriched in cerebellar Purkinje neurons; There was a pervasive upregulation of p-S6 levels in all cerebellar lobules in the Bmal1 heterozygous mutant mice compared to wildtype mice.
Immunohistochemistry
unreported
Regulation of translation2
Abnormal
Description: Bmal1 deletion in the cerebellum led to an altered translational landscape with 304 differentially translated genes (DTGs); Among the DTGs, 6 upregulated and 6 downregulated genes appear in the SFARI database.
Polysome profiling
6-8 weeks
Targeted expression2
Decreased
Description: Bmal1 was enriched in the cerebellum of the wildtype mice, whereas no Bmal1 was detected in the brain of knockout mice.
Immunostaining
6-8 weeks
Differential gene expression2
Abnormal
Description: A total of 444 differentially expressed genes (DEGs) were identified in the knockout cerebellum, comprising 264 upregulated and 180 downregulated genes compared with the wildtype cerebellum.
RNA sequencing
6-8 weeks
Signaling: mTOR pathway2
Increased
Description: Interestingly, double labeling for phospho-S6 and Calbindin-D (28k) revealed cellular colocalization of the two proteins in the PC soma, indicating enriched mTORC1 activities in Purkinje cells; Pervasive upregulation of phospho-S6 was found in all lobules in the knockout mice as compared with the wildtype mice.
Immunostaining
6-8 weeks
Protein expression level evidence2
Decreased
Description: There was differential expression of ATXN3 and ATXN3 proteins.
Western blot
6-8 weeks
Not Reported:
M_BMAL1_3_CKO_HM
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Motor coordination and balance1
Decreased
Description: Conditional knockout mice displayed markedly shorter latencies to fall and fell at slower rotating speeds compared with Bmal1^flox/flox littermates.
Accelerating rotarod test
6-8 weeks
Dendritic architecture: spine morphology1
Abnormal
Description: The fraction of immature dendritic spines was increased but the fraction of mature dendritic spines was decreased in the Purkinje cells of conditional knockout mice.
Golgi-Cox staining
6-8 weeks
Dendritic architecture: spine density1
Increased
Description: The density of dendritic spines in the PC was increased in conditional knockout mice compared with Bmal1^flox/flox littermates.
Golgi-Cox staining
6-8 weeks
Spontaneous post synaptic event amplitude: inhibitory currents1
Increased
Description: There was a two-fold increase in the amplitudes of IPSCs elicited by parallel fiber stimulation in the conditional knockout mice compared with Bmal1^flox/flox littermates.
Whole-cell patch clamp
6-8 weeks
Spontaneous post synaptic event amplitude: excitatory currents1
Increased
Description: There was a two-fold increase in the amplitudes of EPSCs elicited by parallel fiber stimulation in the conditional knockout mice compared with Bmal1^flox/flox littermates. Responses elicited by climbing fiber stimulation were not significantly different between genotypes.
Whole-cell patch clamp
6-8 weeks
Action potential property: firing rate1
Decreased
Description: There was a significant reduction (~30%) of firing rates in the Purkinje cells of the conditional knockout mice compared with Bmal1^flox/flox littermates with or without blocking synaptic inputs into Purkinje cells.
Whole-cell patch clamp
6-8 weeks
Repetitive digging1
Increased
Description: Conditional knockout mice buried more marbles than Bmal1^flox/flox littermates.
Marble-burying test
6-8 weeks
Self grooming1
Increased
Description: Conditional knockout mice exhibited a significantly increased water puff-induced grooming time and number of bouts compared to Bmal1^flox/flox littermates.
Splash test to evoke grooming behavior
6-8 weeks
Social memory1
Decreased
Description: Conditional knockout mice spent similar time in the chamber of and interacting with the novel mouse and familiar mouse, whereas Bmal1^flox/flox littermates spent significantly more time in the chamber with the novel mouse than in the chamber with the familiar mouse; The numbers of entries to the two side chambers were not different between genotypes.
Three-chamber social approach test
6-8 weeks
Targeted expression1
Decreased
Description: Bmal1 expression was diminished in the PCL but not changed in the GL, confirming specific abolition of Bmal1 expression in cerebellar Purkinje cells in the conditional knockout mice.
Immunostaining
6-8 weeks
Signaling: mTOR pathway1
Increased
Description: There was a significant upregulation of phospho-S6 in all lobules of conditional knockout mice compared with Bmal1^flox/flox littermates.
Western blot
6-8 weeks
Circadian rhythms: timing/phases of locomotor activity1
No change
Wheel running monitoring
6-8 weeks
Not Reported:
M_BMAL1_1_KO_HM
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Ultrasonic vocalization: Isolation induced1
Increased
Description: Wildtype mice exhibited a trend of decreasing in the number of calls (p = 0.1181), developing from P7 to P14, but no such trend was found in the Bmal1 homozygous mutant mice. The number of calls was increased in the Bmal1 homozygous pups at P7 and increased in both the Bmal1 mutant pups compared to the wildtype mice at P14. Bmal1 homozygous mutant mice exhibited a longer call duration compared to both Bmal1 heterozygous and wildtype pups at P14.
Monitoring ultrasonic vocalizations
P7, P14
Not Reported:
