Gene-targeting studies of mammalian behavior: is it the mutation or the background genotype?

Gerlai, Robert

doi:10.1016/s0166-2236(96)20020-7

Cited by 829 publications

(529 citation statements)

References 20 publications

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“…A couple of pertinent findings suggest the possibility that lobule VIII‐specific foliation defects may indeed contribute to some of the deficits in motor coordination and learning frequently associated with CHARGE syndrome (Admiraal & Huygen, 1997; Bergman, Janssen et al, 2011; Sanlaville & Verloes, 2007). Lobule VIII is active during sensorimotor tasks (Stoodley & Schmahmann, 2009; Stoodley, Valera, & Schmahmann, 2012) and abnormal motor learning and function have been reported in En2 mutant mice, which have cerebellar vermis foliation defects similar to Chd7 gt/+ mice (Cheh et al, 2006; Gerlai, 1996; Joyner et al, 1991; Millen et al, 1994). However, to date, a correlation between motor dysfunction in CHARGE patients and cerebellar pathology has not been established.…”

Section: Discussionmentioning

confidence: 99%

Distinct cerebellar foliation anomalies in a CHD7 haploinsufficient mouse model of CHARGE syndrome

Whittaker

Kasah

Donovan

et al. 2017

American J of Med Genetics Pt C

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Mutations in the gene encoding the ATP dependent chromatin‐remodeling factor, CHD7 are the major cause of CHARGE (Coloboma, Heart defects, Atresia of the choanae, Retarded growth and development, Genital‐urinary anomalies, and Ear defects) syndrome. Neurodevelopmental defects and a range of neurological signs have been identified in individuals with CHARGE syndrome, including developmental delay, lack of coordination, intellectual disability, and autistic traits. We previously identified cerebellar vermis hypoplasia and abnormal cerebellar foliation in individuals with CHARGE syndrome. Here, we report mild cerebellar hypoplasia and distinct cerebellar foliation anomalies in a Chd7 haploinsufficient mouse model. We describe specific alterations in the precise spatio‐temporal sequence of fissure formation during perinatal cerebellar development responsible for these foliation anomalies. The altered cerebellar foliation pattern in Chd7 haploinsufficient mice show some similarities to those reported in mice with altered Engrailed, Fgf8 or Zic1 gene expression and we propose that mutations or polymorphisms in these genes may modify the cerebellar phenotype in CHARGE syndrome. Our findings in a mouse model of CHARGE syndrome indicate that a careful analysis of cerebellar foliation may be warranted in patients with CHARGE syndrome, particularly in patients with cerebellar hypoplasia and developmental delay.

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Section: Discussionmentioning

confidence: 99%

Distinct cerebellar foliation anomalies in a CHD7 haploinsufficient mouse model of CHARGE syndrome

Whittaker

Kasah

Donovan

et al. 2017

American J of Med Genetics Pt C

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“…Since no difference in ischemic stress was noted, as revealed by CBF and anoxic depolarization, these results suggest that p53 potentiates the ischemic neuronal death. Generally, gene-engineered mice are generated from multiple genetic backgrounds (Gerlai, 1996). The original chimera used to generate the mutant mice in this study was made from C57BL/6 and SV129 strains, which differ in their vulnerability to ischemia (Yonekura et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…The original chimera used to generate the mutant mice in this study was made from C57BL/6 and SV129 strains, which differ in their vulnerability to ischemia (Yonekura et al, 2004). However, all mutant mice used were backcrossed with C57BL/6 mice for 12 generations from the original chimera, theoretically eliminating 99% of the SV129 background (Gerlai, 1996). Thus, it is unlikely that our results were affected by genetic differences other than the absence of one or both p53 alleles in the mutant mice.…”

Section: Discussionmentioning

confidence: 99%

p53 Potentiates Hippocampal Neuronal Death Caused by Global Ischemia

Yonekura

Takai

Asai

et al. 2006

J Cereb Blood Flow Metab

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Although p53 controls cell death after various stresses, its role in neuronal death after brain ischemia is poorly understood. To address this issue, we subjected p53-deficient (p53 À/À and p53 + /-) mice (backcrossed for 12 generations with C57BL/6 mice) and wild-type mice (p53 + / + ) to transient global ischemia by the three-vessel occlusion method. Despite similar severity of ischemia, as shown by anoxic depolarization and cortical blood flow, neuronal death in the hippocampal cornus ammonis (CA)1 region was much more extensive in p53 + / + than in p53 À/À mice (surviving neuronal count, 9.3%63.0% versus 61.3%634.0% of nonischemic p53 + / + controls, respectively, P < 0.0037). In p53 + /À mice, a similar trend was also observed, though not statistically significant (43.5% of nonischemic p53 + / + controls). In p53 + / + mice, p53-like immunoreactivity in hippocampal CA1 neurons was enhanced at 12 h after ischemia, and messenger ribonucleic acid for Bax, a direct downstream target of p53, was also increased. These results indicate that p53 potentiates ischemic neuronal death in vivo and suggest that this molecule could be a therapeutic target in neuronal death after cerebral ischemia.

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“…One possible explanation for the lack of agreement between targeted gene deletion and pharmacological inhibition of the 5-HT 3 receptor is that developmental compensation occurred in the null mutants, which may have masked any functional involvement of the receptor subunit in alcohol drinking. Compensation may be due to genetic redundancy whereby so-called 'helper' genes can take over the function of the targeted gene (Gerlai, 1996;Gerlai, 2001). Thus, it is possible that the 5-HT 3A receptor subunit is an important mediator of alcohol drinking, but compensation by another unknown pathway concealed this involvement.…”

Section: -Ht 3 Antagonist-induced Reductions In Alcohol Drinkingmentioning

confidence: 99%

5-HT3A Receptor Subunit is Required for 5-HT3 Antagonist-Induced Reductions in Alcohol Drinking

Hodge

Kelley

Bratt³

et al. 2004

Neuropsychopharmacol

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The ionotropic serotonin subtype-3 (5-HT 3 ) receptor has emerged as a potential therapeutic target in the treatment of alcohol abuse and alcoholism because selective pharmacological antagonists reduce alcohol consumption in preclinical and clinical models. 5-HT binds to the extracellular N-terminus of the 5-HT 3A receptor subunit but receptor activation is also enhanced by distinct allosteric sites, which indicates the presence of other receptor subunits. It is not known if specific molecular subunits of the 5-HT 3 receptor modulate alcohol drinking. To address this issue, we characterized acute locomotor response to alcohol and alcohol consumption in a two-bottle homecage procedure by congenic C57BL/6J mice with a targeted deletion of the 5-HT 3A receptor subunit gene. 5-HT 3A -null mice did not differ from wild-type littermate controls on measures of spontaneous locomotor activity, habituation to a novel environment, or locomotor response to ethanol (0, 0.5, 1, or 2 g/kg). Moreover, null mice did not differ from controls on measures of ethanol (2-10%) intake and preference during or after a two-bottle home-cage sucrose fading procedure. Systemic administration of the 5-HT 3 antagonist LY-278,584 (0-10 mg/kg) decreased intake of both sweetened (2% sucrose þ 10% ethanol) and unsweetened (10% ethanol) ethanol in wild-type mice only. These findings indicate that reduction of alcohol drinking produced by 5-HT 3 antagonism is dependent on the presence of 5-HT 3A -containing receptors.

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Gene-targeting studies of mammalian behavior: is it the mutation or the background genotype?

Cited by 829 publications

References 20 publications

Distinct cerebellar foliation anomalies in a CHD7 haploinsufficient mouse model of CHARGE syndrome

Distinct cerebellar foliation anomalies in a CHD7 haploinsufficient mouse model of CHARGE syndrome

p53 Potentiates Hippocampal Neuronal Death Caused by Global Ischemia

5-HT3A Receptor Subunit is Required for 5-HT3 Antagonist-Induced Reductions in Alcohol Drinking

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