Table 1.
Genetic Mammalian Models of the NCOAs and NCORs
Genetic Manipulation | Phenotype | Ref. |
---|---|---|
NCOA1 knockdown | NCOA1 ASO blunted defeminizing actions of androgen in female rats and increased lordosis in male rats. | (37) |
NCOA1 or NCOA2 knockdown of in the VMH in adult female rats reduced the estradiol/progesterone-induced lordosis behaviors. | (38) | |
NCOA1 knockdown in the VMH reduced progesterone-induced ear wiggling, hopping, and darting behaviors in female rats. | (39) | |
NCOA1 knockdown using lentivirus small hairpin RNA in the nucleus of the solitary tract in OVX female rats increased food intake and body weight in the presence of 17β-estradiol administration. | (48) | |
NCOA1 knockdown in the adult mouse hippocampus through injection of the lentiviral shRNA impaired spatial learning and memory, decreased the CA1 synapse density, and impaired long-term potentiation. | (69) | |
NCOA1 splicing isoform switch | Injection of “exon-skipping” ASO targeting on in the CeA increased NCOA1a/1e ratio, blunted glucocorticoid-induced exploratory behavior, and attenuated context-dependent fear memory. | (55, 56) |
NCOA1 global knockout | NCOA1-/- mice show blunted effects of 17β-estradiol in reducing food intake and body weight in OVX female mice. | (41) |
NCOA1-/- mice show elevated circulating corticosterone despite normal ACTH after exposure to stress, suggesting defective glucocorticoid-mediated feedback inhibition in the CNS. | (52) | |
NCOA1-/- mice display lower basal CRH gene expression in the CeA and upregulated hypothalamic CRH expression after chronic stress. | (53) | |
NCOA1-/- mice display elevated circulating levels of TSH, T4, and T3, and required higher doses of T3 to suppress TSH and T4, suggesting reduced sensitivity of the thyrotrophs in the anterior pituitary to TH. | (63, 64) | |
NCOA1-/- mice show reduced anxiety, impaired motor learning, and lower pain threshold in males. | (31, 50) | |
NCOA1L1376P knock-in | NCOA1L1376P knock-in mice bearing a mutation identified in obese patients show decreased leptin-induced depolarization of POMC neurons, increased food intake, and exacerbated obesity. | (42) |
NCOA2 global knockout | NCOA2-/- mice show lower body weight, lower anxiety, impaired motor learning and motor coordination, and higher pain threshold in females. NCOA2-/- male mice show deficits in sensorimotor gating. | (50) |
NCOA2-/- mice show disrupted diurnal rhythm in locomotor activity and food intake behaviors, with abnormally elevated physical activity occurring late in the light phase. | (49) | |
NCOA3 global knockout | NCOA3-/- mice show reduced amino acid levels in the brain, with increased anxiety behaviors in females, and higher pain threshold in both sexes. | (50,13) |
NCOR1 knockdown | NCOR1 knockdown in the amygdala by siRNA in rats increases juvenile social play behaviors in males and anxiety-like behaviors in both males and females. Social interaction in the three-chamber assay is normal in these rats. | (60) |
NCOR1 truncation | Global deletion of the last few exons of NCOR1 (NCOR1ΔID) in mice leads to lower circulating TH levels without a compensatory increase in TSH production. Pituitary-specific expression of NCOR1ΔID shows a similar phenotype. | (66,67) |
NCOR1Y478A NCOR2Y470A (NS-DADm) | NS-DADm mice show increased activity, enhanced locomotor coordination, reduced anxiety, impaired social interaction, and impaired spatial learning and recognition memory. | (70) |
Vgat-Cre; NCOR1loxP; NCOR2loxP | NS-V mice show impaired learning and memory due to hyperexcitability of the lateral hypothalamus to hippocampal CA3 neural projection. | (70) |
Virus-mediated region-specific deletion of HDAC3 | HDAC3 depletion in the adult hippocampal CA1 region enhances long-term memory formation (71). | (71) |
HDAC3 depletion in the adult lateral hypothalamus impairs memory, while HDAC3 depletion in the adult hippocampal CA3 region does not affect memory. | (70) | |
HDAC3 depletion in the nucleus accumbens enhances cocaine-induced conditioned place preference (CPP) acquisition. | (72) | |
HDAC3 depletion in retinal ganglion cells (RGC) in adult mice ameliorates cell death, heterochromatin formation, nuclear envelope breakdown, and nuclear pore damage in RGCs following optic nerve crush. | (73) | |
Nestin-Cre, HDAC3loxP | These mice show abnormal cytoarchitecture of the neocortex and cerebellum that leads to lethality within a day after birth. | (75) |
Camk2a-Cre, HDAC3loxP | These mice show neuron loss in the hippocampus, hyperactivity, abnormal exploratory behavior, hind limb clasping, sociability deficits, and impaired memory, with reduced FOXO activity. A separate study reports progressive hindlimb paralysis, ataxia, higher numbers of astrocytes, and Purkinje neuron degeneration, which leads to lethality at ~ 6 weeks old. | (75, 76) |
Emx1-Cre, HDAC3loxP | Cerebrum-specific depletion of HDAC3 causes abnormal neocortical lamination and hippocampal development, premature neurogenesis, disrupts neuronal migration, augmented DNA damage response and apoptosis, which contribute to depletion of neural stem and progenitor cells (NSPCs). | (77) |
Abbreviations: ACTH, adrenocorticotropic hormone; ASO, antisense oligodeoxynucleotides; CeA, central nucleus of amygdala; CRH, corticotropin-releasing hormone; HDAC, histone deacetylase; NCOA, nuclear receptor coactivator; NCOR, nuclear receptor repressor; OVX, ovariectomized; POMC, proopiomelanocortin; T3, triiodothyronine; T4, thyroxine; TH, thyroid hormone; TSH, thyrotropin (thyroid-stimulating hormone); VMH, ventromedial hypothalamus