Abnormal Long-Lasting Synaptic Plasticity and Cognition in Mice Lacking the Mental Retardation Gene<i>Pak3</i>

Meng, Jinsong; Meng, Yanghong; Hanna, Amanda; Janus, Christopher; Jia, Zhengping

doi:10.1523/jneurosci.0028-05.2005

Cited by 175 publications

(180 citation statements)

References 71 publications

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“…More recently, mice lacking the PAK3 gene were generated, and analysis of these mice showed selective impairment in late-phase hippocampal LTP, a distinct form of long-term synaptic plasticity involving new gene expression. Surprisingly, in this mice knockout model, no obvious deficits in neuronal structures were observed [57]. The differences seen with regards to spine morphology between the knockout and RNAi studies could potentially reflect differences between a homogeneous and a heterogeneous cell population, respectively, or could be attributed to compensatory mechanisms in the knockout mice.…”

Section: Pak3mentioning

confidence: 68%

Rho-linked genes and neurological disorders

Kasri

Aelst

2007

Pflugers Arch - Eur J Physiol

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Mental retardation (MR) is a common cause of intellectual disability and affects approximately 2 to 3 % of children and young adults. MR has been consistently associated with changes in dendrites and dendritic spine structure. Given that dendritic spine morphology has been tightly linked to synaptic activity, altered spine morphology has been suggested to be the underlying cause of cognitive disabilities observed in MR. The structure and dynamics of dendritic spines is determined by its underlying actin cytoskeleton. Signaling molecules and cascades important for cytoskeletal regulation have therefore naturally attracted a great deal of attention. As key regulators of both the actin and microtubule cytoskeletons, it is not surprising that the Rho GTPases have emerged as important regulators of dendrite and spine structural plasticity. In support of this, mutations in regulators and effectors of Rho GTPases have been associated with diseases affecting the nervous system, including MR and amyotropic lateral sclerosis (ALS). Here we will discuss Rho GTPase related genes and their signaling pathways involved in MR and ALS.

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Section: Pak3mentioning

confidence: 68%

Rho-linked genes and neurological disorders

Kasri

Aelst

2007

Pflugers Arch - Eur J Physiol

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“…46 For PAK3 (p21-activated kinase), a member of PAK protein family that are activated by the two small RhoGTPases Rac and Cdc42 (cell division cycle 42 ), the contribution in synapse formation and plasticity was clearly demonstrated by two groups. 44,45 Using transient 45 showed that PAK3 is localized at dendritic spines, and that PAK3 inactivation results in formation of abnormal dendritic spines and a reduced spontaneous synaptic activity and defective long-term potentiation (LTP). Meng et al 44 generated a knockout mice model deficient for PAK3 and showed that this model exhibits significant abnormalities in synaptic plasticity, especially hippocampal late-phase LTP, and deficiencies in learning and memory.…”

Section: Synaptic Structure and Function And Mental Retardationmentioning

confidence: 99%

Genetics and pathophysiology of mental retardation

et al. 2006

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Mental retardation (MR) is defined as an overall intelligence quotient lower than 70, associated with functional deficit in adaptive behavior, such as daily-living skills, social skills and communication. Affecting 1-3% of the population and resulting from extraordinary heterogeneous environmental, chromosomal and monogenic causes, MR represents one of the most difficult challenges faced today by clinician and geneticists. Detailed analysis of the Online Mendelian Inheritance in Man database and literature searches revealed more than a thousand entries for MR, and more than 290 genes involved in clinical phenotypes or syndromes, metabolic or neurological disorders characterized by MR. We estimate that many more MR genes remain to be identified. The purpose of this review is to provide an overview on the remarkable progress achieved over the last decade in delineating genetic causes of MR, and to highlight the emerging biological and cellular processes and pathways underlying pathogeneses of human cognitive disorders.

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“…5 -8 PAK3 gene transcripts encode p21-activated kinase (PAK) protein isoforms shown to be critical downstream rGTPases effectors that link Rac1 and Cdc42 to actin cytoskeleton and MAP kinases cascades. 5,9 The most investigated PAK3 protein isoform contains 544 amino acids with two critical domains, consisting of an N-terminal regulatory region that includes a CRIB motif that binds to GTP bound forms of Cdc42 and Rac1, and a C-terminal catalytic domain with a serine/threonine (STK) protein kinase domain. 10 To our knowledge, the described PAK3 mutations include one nonsense mutation (p.R419X) and three missense mutations located either in the regulatory or the catalytic domain without any evidence of correlation with the severity of the phenotype.…”

Section: Introductionmentioning

confidence: 99%

A novel splice mutation in PAK3 gene underlying mental retardation with neuropsychiatric features

et al. 2008

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PAK3-related mental retardation represents a rare cause of X-linked mental retardation associated with behavioural symptoms. So far, four families carrying PAK3 mutations have been reported, and in most cases PAK3 dysfunction resulted from missense mutations thought to affect either the catalytic or the N-terminal regulatory domain activity. Here, we report on a Tunisian family of X-linked moderate mental retardation with behavioural symptoms, common dysmorphic features, oro-motor impairment and secondary microcephaly. Linkage analysis showed that affected male subjects and obligate carrier female subjects share a common haplotype in the Xp21.31 -Xq23 region that contains the PAK3 gene. Direct sequencing of PAK3 coding exons and flanking intronic sequences allowed us to identify the first splice mutation in PAK3 gene located at the 5 0 end of intron 6 (c.276 þ 4A4G), which results in a complete switch-off of the genuine donor splice site and an activation of a cryptic donor splice site (GTAAG) located four nucleotides downstream to the genuine one. RT-PCR experiments using the RNA from the patient's lymphoblasts showed that PAK3 transcripts contain four additional nucleotides that lead to a disruption of reading frame with a premature stop codon at position 128. Together with previously reported observations, our data further confirm that PAK3 mutations result in a specific form of X-linked mental retardation with fairly constant clinical features.

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Abnormal Long-Lasting Synaptic Plasticity and Cognition in Mice Lacking the Mental Retardation GenePak3

Cited by 175 publications

References 71 publications

Rho-linked genes and neurological disorders

Rho-linked genes and neurological disorders

Genetics and pathophysiology of mental retardation

A novel splice mutation in PAK3 gene underlying mental retardation with neuropsychiatric features

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