Negr1 knockout mice displayed abnormal neuronal growth, impaired social behavior, reversal learning deficits, and increased susceptibility to pentylenetetrazol (PTZ)-induced seizures (Singh et al., 2018). siRNA-mediated downregulation of Negr1 in mice resulted in abnormal neuronal migration and spine density during cortical development, as well as reduced ultrasonic vocalizations and impaired social interactions; Negr1 knockout mice presented with similar phenotypes (Szczurkowska et al., 2018). A 1p31.1 microdeletion affecting the NEGR1 gene was identified in two siblings presenting with learning disabilities, ADHD, and autistic features (Genovese et al., 2015).
Molecular Function
May be involved in cell-adhesion. May function as a trans-neural growth-promoting factor in regenerative axon sprouting in the mammalian brain
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Neuronal Growth and Behavioral Alterations in Mice Deficient for the Psychiatric Disease-Associated Negr1 Gene.
ASD cohort: 18,381 cases and 27,969 controls from iPSYCH and the Psychiatric Genomic Consortium (PGC). MTAG: 18,381 ASD cases and 27,969 controls, in addition to 135,458 MDD cases and 344,901 controls from Wray et al., 2018 (PMID 29700475)
NEGR1 knockout mice show abnormalities of EC axons in the hippocampal dentate gyrus including increased numbers of axonal projections to the hilus. NEGR1 knockout mice show no change in neurotransmitter receptor ligand binding densities. However Negr1 knockout mice show altered ligand binding densities to NMDA receptor and muscarinic acetylcholine receptors M1 and M2 in CA1 and CA3. Negr1 KO mice show no change in activity behavior, anxiety-like behavior and sensorimotor gating however, Negr1 KO mice exhibited impaired social behavior, deficits in reversal learning, deficits in the Morris water maze together with increased susceptibility to PTZ-induced seizures (Singh K., Front. Mol. Neuro., 2018).
References
Type
Title
Author, Year
Primary
Neuronal Growth and Behavioral Alterations in Mice Deficient for the Psychiatric Disease-Associated Negr1 Gene.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The mouse Negr1 gene was mutated in embryonic stem (ES) cells by replacement of exon 2, which encodes the first Ig-like domain and the 3' exon/intron splice site, with a neomycin resistance cassette on the C57Bl/6 background.
Allele Type: Targeted knockout
Strain of Origin: C57Bl/6
Genetic Background: C57Bl/6
ES Cell Line: Mutant ES Cell Line: Model Source: Lee AWS et al, PlosOne, 2012 (PMID 22844493)
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The mouse Negr1 gene was mutated in embryonic stem (ES) cells by replacement of exon 2, which encodes the first Ig-like domain and the 3' exon/intron splice site, with a neomycin resistance cassette on the mixed 129S5/SvEvBrd_C57BL/6 background.
Allele Type: Targeted knockout
Strain of Origin: Genetic Background: 129S5/SvEvBrd_C57BL/6
ES Cell Line: Mutant ES Cell Line: Model Source: Lee AWS et al, PlosOne, 2012 (PMID 22844493)
Model Type:
Genetic
Model Genotype:
NA
Mutation:
E15.2 timed-pregnant CD1 mice were injected with Negr1 siRNA in Fast Green dye through the uterine wall into the lateral ventricle of each embryo and electroporated into the sub-ventricular zone of the cortex. Co-electroporation of td-Tomato or EGFP was used to visualize transfected neurons and normalize total DNA transfected.
Allele Type: Knockdown
Strain of Origin: CD1
Genetic Background: CD1
ES Cell Line: Mutant ES Cell Line: Model Source: Charles River, SRL
Model Type:
Genetic
Model Genotype:
NA
Mutation:
E15.2 timed-pregnant CD1 mice were injected with Negr1 siRNA in Fast Green dye through the uterine wall into the lateral ventricle of each embryo and electroporated into the visual cortex. Co-electroporation of td-Tomato or EGFP was used to visualize transfected neurons and normalize total DNA transfected.
Allele Type: Knockdown
Strain of Origin: CD1
Genetic Background: CD1
ES Cell Line: Mutant ES Cell Line: Model Source: Charles River, SRL
Model Type:
Genetic
Model Genotype:
NA
Mutation:
E15.2 timed-pregnant CD1 mice were injected with Negr1 siRNA in Fast Green dye through the uterine wall into the lateral ventricle of each embryo and electroporated into the motor and somatosensory cortices. Co-electroporation of td-Tomato or EGFP was used to visualize transfected neurons and normalize total DNA transfected.
Allele Type: Knockdown
Strain of Origin: CD1
Genetic Background: CD1
ES Cell Line: Mutant ES Cell Line: Model Source: Charles River, SRL
Model Type:
Genetic
Model Genotype:
NA
Mutation:
E15.2 timed-pregnant CD1 mice were injected with Negr1 siRNA in Fast Green dye through the uterine wall into the lateral ventricle of each embryo and electroporated into the prefrontal cortex. Co-electroporation of td-Tomato or EGFP was used to visualize transfected neurons and normalize total DNA transfected.
Allele Type: Knockdown
Strain of Origin: Genetic Background: ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
The mouse Negr1 gene was mutated in embryonic stem (ES) cells by replacement of exon 2, which encodes the first Ig-like domain and the 3' exon/intron splice site, with a neomycin resistance cassette on the C57Bl/6 background.
Allele Type: Targeted knockout
Strain of Origin: C57Bl/6
Genetic Background: C57Bl/6
ES Cell Line: Mutant ES Cell Line: Model Source: Lee AWS et al, PlosOne, 2012 (PMID 22844493)
Description: Mutants show decreased fasciculation of axons in the molecular layer of the dentate gyrus compared with controls.
Exp Paradigm: To trace entorhinal axons in the brain, dii-crystals were positioned into the upper layers of the ec in fixed transversal tissue blocks. 3 weeks later, diffusion of the neuronal tracer was observed in the major entorhino-hippocampal pathways, the alvear path and the perforant path.
Description: Mutants show increased nmdar ligand binding in the stratum oriens and stratum radiatum in the ca1 region compared with controls.
Exp Paradigm: NA
Description: Negr1 constitutive null mice show a shift in the distribution of cux1-positive upper cortical layer neurons towards layer v in thesomatosensory cortex compared to controls, and ectopic location of cux1 positive cells in cortical layer v.
Exp Paradigm: NA
Description: Mutants show dii labeled axons crossing the inner molecular layer and approaching and traversing beyond the granular cell layer into the hilar region compared with controls.
Exp Paradigm: To trace entorhinal axons in the brain, dii-crystals were positioned into the upper layers of the ec in fixed transversal tissue blocks. 3 weeks later, diffusion of the neuronal tracer was observed in the major entorhino-hippocampal pathways, the alvear path and the perforant path.
Description: Mutants show slightly increased mach m1r ligand binding in ca1 stratum radiatum and ca3 pyramidal cell layer compared with controls.
Exp Paradigm: NA
Description: Mutants show increased susceptibility to chemically (ptz) induced seizures compared with controls with shorter latency to stage 1 (hypoactivity), a trend towards shorter latency to stage 2 (head nodding), stage 3 (forelimb clonus), and stage 4 (generalized seizures), an increase in the percentage of mice exhibiting seizures, and an increase in the seizure score calculated over all four stages.
Exp Paradigm: Mouse behavior was monitored for 30 min aftersingle administration of ptz
Description: Negr1 constitutive null mice show decrease in social sniffing during juvenile play with an unfamiliar mouse compared with controls.
Exp Paradigm: NA
Description: Mutants show no co-immunoprecipitation of fgfr2 when negr1 is immunoprecipitated compared to wildtype that show co-immunoprecipitation of fgfr2 when negr1 is immunoprecipitated from brain lysates.
Exp Paradigm: NA
Description: Mutants show decreased ability to find the hidden platform in the first three trials compared with controls but performed similar to controls on the fourth trial, indicating mutants are slow learners.
Exp Paradigm: NA
Description: Mutants show decrease in time spent in the changed quadrant after reversal training compared with controls, indicating mutants have impaired relearning capacity.
Exp Paradigm: NA
Description: Negr1 knockdown neurons that were stuck in layer v at p7 retained markers of the upper layers ii/iii (cux1) indicating mis-specification of cortical layer specific neurons.
Exp Paradigm: NA
Description: Negr1 knockdown neurons were mostly located in the ventricular zone and intermediate zone, with only a small percentage reaching the cortical plate at e18 whereas control scrambled sirna cells were distributed across the ventricular zone, intermediate zone, and cortical plate, indicating reduced radial migration of negr1 knockdown neurons. negr1 knockdown neurons were stuck in layer v and did not cross the border between layer iv/v by p7 or p35, whereas most control sirna transfected neurons migrated into layer ii/ii. negr1 knockdown neurons of upper cortical layers accumulated in lower subregions compared to controls.
Exp Paradigm: NA
Dendritic architecture: dendritic tree complexity1
Decreased
Description: Negr1 knockdown neurons in the somatosensory cortex and ectopic neurons stuck in layer v show decrease in the number of dendritic branches compared to controls.
Exp Paradigm: NA
Description: Negr1 knockdown neurons in layer ii/iii of the somatosensory cortex and ectopic neurons stuck in layer v show decrease in dendritic length compared to controls.
Exp Paradigm: NA
Description: Negr1 knockdown neurons were ectopically located in the visual cortex and mis-positioned in layer ii/iii compared to controls.
Exp Paradigm: NA
Description: Negr1 knockdown neurons with electroporation targeting neurons in the visual cortex show decrease in spine density compared to controls.
Exp Paradigm: NA
Description: Negr1 knockdown neurons in the motor and somatosensory cortices were ectopically located in layer v compared to controls. defect is neuronal migration was higher in the somatosensory cortex than in the motor cortex (wildtype negr1 expression is stronger in the somatosensory and visual cortices than in the motor cortex).
Exp Paradigm: NA
Description: Negr1 knockdown neurons with electroporation targeting layer ii/iii neurons in the somatosensory cortex show decrease in spine density compared to controls.
Exp Paradigm: NA
Description: Pups transfected with negr1 sirna in the somatosensory cortex show increased latency in removing paw from hot plate compared to controls.
Exp Paradigm: NA
Description: Pups transfected with negr1 sirna into the somatosensory cortex show decrease in ultrasonic vocalizations compared to controls.
Exp Paradigm: NA
Description: Negr1 constitutive null het mice show decrease in social sniffing during juvenile play with an unfamiliar mouse compared with controls.
Exp Paradigm: NA
