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author:("Lim, bongshin")
1.  Distinct DNA binding and transcriptional repression characteristics related to different ARX mutations 
Neurogenetics  2012;13(1):23-29.
Mutations in the Aristaless-related homeobox gene (ARX) are associated with a wide variety of neurologic disorders including lissencephaly, hydrocephaly, West syndrome, Partington syndrome, and X-linked intellectual disability with or without epilepsy. A genotype-phenotype correlation exists for ARX mutations, however the molecular basis for this association has not been investigated. To begin understanding the molecular basis for ARX mutations, we tested the DNA binding sequence preference and transcriptional repression activity for Arx, deletion mutants and mutants associated with various neurologic disorders. We found DNA binding preferences of Arx are influenced by the amino acid sequences adjacent to the homeodomain. Mutations in the homeodomain show a loss DNA binding activity, while the T333N and P353R homeodomain mutants still possess DNA binding activities, although less than wild type. Transcription repression activity, the primary function of ARX, is reduced in all mutants except the L343Q, which has no DNA binding activity and does not functionally repress Arx targets. These data indicate that mutations in the homeodomain result in not only a loss of DNA binding activity but also loss of transcriptional repression activity. Our results provide novel insights into the pathogenesis of ARX related disorders and possible directions to pursue potential therapeutic interventions.
doi:10.1007/s10048-011-0304-7
PMCID: PMC3279587  PMID: 22252899
ARX; lissencephaly; X-linked intellectual disability and Homeodomain
2.  XLMR candidate mouse gene, Zcchc12 (Sizn1) is a novel marker of Cajal-Retzius cells 
Gene expression patterns : GEP  2010;11(3-4):216-220.
Sizn1 (Zcchc12) is a transcriptional co-activator that positively modulates BMP (Bone Morphogenic Protein) signaling through its interaction with Smad family members and CBP. We have demonstrated a role for Sizn1 in basal forebrain cholinergic neuron specific gene expression. Furthermore, mutations in SIZN1 have been associated with X-linked mental retardation. Given the defined role of SIZN1 in mental retardation, knowing its complete forebrain expression pattern is essential to further elucidating its role in cognition. To better define the dynamic expression pattern of Sizn1 during forebrain development, we investigated its expression in mouse brain development from embryonic day 8.0 (E8.0) to adult. We found that Sizn1 is primarily restricted to the ventral forebrain including the medial ganglionic eminence, the septum, amygdala, and striatum. In addition, Sizn1 expression is detected in the cortical hem and Pallial-subpallial boundary (PSB; anti-hem); both sources of Cajal-Retzius cells. Sizn1 expression in the dorsal forebrain is restricted to a subset of cells in the marginal zone that also express Reln, indicative of Cajal-Retzius cells. These data provide novel information on brain regions and cell types that express Sizn1, facilitating further investigations into the function of Sizn1 in both development and the pathogenesis of mental retardation.
doi:10.1016/j.gep.2010.12.005
PMCID: PMC3065530  PMID: 21172456
3.  α-syn Suppression Reverses Synaptic and Memory Defects in a Mouse Model of Dementia with Lewy Bodies 
Abnormally accumulated α-syn is a pathological hallmark of Lewy body related disorders such as Parkinson’s disease (PD) and Dementia with Lewy body disease (DLB). However, it is not well understood whether and how abnormal accumulation of α-syn leads to cognitive impairment or dementia in PD and DLB. Furthermore, it is not known whether targeted removal of α-syn pathology can reverse cognitive decline. Here we find that the distribution of α-syn pathology in an inducible α-syn transgenic mouse model recapitulates that in human DLB. Abnormal accumulation of α-syn in the limbic system, particularly in the hippocampus, correlated with memory impairment and lead to structural synaptic deficits. Furthermore, when α-syn expression was suppressed, we observed partial clearing of pre-existing α-syn pathology and reversal of structural synaptic defects, resulting in an improvement in memory function.
doi:10.1523/JNEUROSCI.0618-11.2011
PMCID: PMC3144489  PMID: 21734300
4.  Forebrain Overexpression of Alpha-Synuclein Leads to Early Postnatal Hippocampal Neuron Loss and Synaptic Disruption 
Experimental neurology  2009;221(1):86-97.
Transgenic (Tg) mouse models of Parkinson’s disease (PD) generated to date have primarily been designed to overexpress human alpha-synuclein (α–syn) to recapitulate PD-like motor impairments as well as PD-like nigro-striatal degeneration and α–syn pathology. However, cognitive impairments and cortical α–syn pathology also are common in PD patients. To model these features of PD, we created forebrain-specific conditional Tg mice that overexpress human wild type (WT) or A53T mutant α–syn. Here we show that both WT and A53T mutant α–syn lead to massive degeneration of postmitotic neurons in the hippocampal dentate gyrus (DG) during postnatal development, with hippocampal synapse loss as evidenced by reduced levels of pre- and postsynaptic markers. However, when mutant and WT α–syn expression was repressed until the Tg mice were mature postnatally and then induced for several months, no hippocampal neuron loss was observed. These data imply that developing neurons are more vulnerable to degenerate than mature neurons as a consequence of forebrain WT and mutant α–syn overexpression.
doi:10.1016/j.expneurol.2009.10.005
PMCID: PMC2812632  PMID: 19833127
α -synuclein; Parkinson’s disease; conditional transgenic mouse; hippocampus; dentate gyrus; postnatal development
5.  Sizn1 Is a Novel Protein That Functions as a Transcriptional Coactivator of Bone Morphogenic Protein Signaling▿ § 
Molecular and Cellular Biology  2007;28(5):1565-1572.
Bone morphogenic proteins (BMPs) play pleotrophic roles in nervous system development, and their signaling is highly regulated at virtually every step in the pathway. We have cloned a novel gene, Sizn1 (Smad-interacting zinc finger protein), which functions as a transcriptional coactivator of BMP signaling. It positively modulates BMP signaling by interacting with Smad family members and associating with CBP in the transcription complex. Sizn1 is expressed in the ventral embryonic forebrain, where, as we will show, it contributes to BMP-dependent, cholinergic-neuron-specific gene expression. These data indicate that Sizn1 is a positive modulator of BMP signaling and provide further insight into how BMP signaling can be modulated in neuronal progenitor subsets to influence cell-type-specific gene expression and development.
doi:10.1128/MCB.01038-07
PMCID: PMC2258788  PMID: 18160706

Results 1-5 (5)