東華大學圖書館 |

Neuron-Specific Chromatin Remodeling in Social Behavior and Memory.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Neuron-Specific Chromatin Remodeling in Social Behavior and Memory./
作者:	Wenderski, Wendy Christine.
面頁冊數:	1 online resource (210 pages)
附註:	Source: Dissertations Abstracts International, Volume: 84-05, Section: B.
Contained By:	Dissertations Abstracts International84-05B.
標題:	Stem cells. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=29755799click for full text (PQDT)
ISBN:	9798357528452

Neuron-Specific Chromatin Remodeling in Social Behavior and Memory.
Wenderski, Wendy Christine.

Neuron-Specific Chromatin Remodeling in Social Behavior and Memory. - 1 online resource (210 pages)

Source: Dissertations Abstracts International, Volume: 84-05, Section: B.

Thesis (Ph.D.)--Stanford University, 2022.

Includes bibliographical references

Within the nucleus, DNA is packaged with histones and other proteins to form chromatin. This serves to protect and organize the genome, and to regulate processes like transcription. The BAF ATP-dependent chromatin remodeling complex controls the accessibility of DNA-and thus, transcription-by mobilizing histones and evicting Polycomb repressive complexes. Mutations in BAF subunits are enriched among individuals with neurodevelopmental disorders that feature intellectual disability and impaired social communication. Yet, how BAF mutations cause neurological symptoms, and more generally, how chromatin remodeling contributes to brain function, is poorly understood. This thesis work reveals BAF mechanisms in three neurodevelopmental disorders: autism, Down syndrome and Baraitser-Winter syndrome.Autism spectrum disorder (ASD) is a prevalent group of neurodevelopmental disorders that are defined by social deficits and restricted or repetitive behavior. Core BAF subunits including ARID1B are among the most frequently mutated genes in ASD, but the causal mechanisms are unknown. I hypothesized that BAF mutant ASD arises from impaired function of the neuronal BAF complex, which is defined by subunits ACTL6B, DPF1/3, and SS18L1. If true, mutations in neuronal-specific subunits would be expected to cause ASD. Whole exome sequencing revealed ACTL6B as the most significantly mutated gene in the Simons Recessive Autism Cohort, with loss-of-function mutations causing fully-penetrant Mendelian recessive ASD. Actl6b-/- mice on two genetic backgrounds exhibited patient-related social and memory impairments, stereotypies, hyperactivity, and corpus callosum hypogenesis, a clinical characteristic of BAF mutant ASD thought to arise from axonal targeting defects. I demonstrated a conserved role for ACTL6B in neural circuit formation by genetic complementation in fly olfactory projection neurons, where neurons expressing patient variants projected to the wrong glomerulus with 100% penetrance. These findings unveiled ACTL6B loss as a highly penetrant cause of Mendelian ASD, with conserved phenotypes in mouse and fly.Experiments using the Actl6b-/- mouse model have provided insight into molecular and cellular mechanisms. First, analysis of "resting state" gene expression and chromatin accessibility in network-silenced Actl6b-/- cortical neurons revealed signatures of activity like FOS expression, indicating a role for BAF in stabilizing resting state transcription. Second, genes involved in neurite targeting (e.g., semaphorins) and social behavior (e.g., serotonin receptor 1b; 5-HT1b) showed altered expression in Actl6b-/- neurons. Systemic administration of a 5-HT1b agonist fully rescued social impairments and hyperactivity in Actl6b-/- mice. Conditional deletion of the autism-related BAF subunit Arid1b in mouse serotonergic neurons caused social impairments that were rescued with the 5-HT1b agonist, indicating that serotonin-specific BAF chromatin remodeling is necessary for social behavior and facilitates pro-social neurotransmission. The 5-HT1b agonist rescued social behavior in 4 additional diverse mouse models for autism, indicating insufficient serotonin neurotransmission as a convergent and potentially causative mechanism for ASD.Through my studies of neuronal BAF, I identified the putative histone "reader" BRWD1 as a substoichiometric subunit and found that BRWD1 contributed to memory, transcriptional, and BAF targeting defects in a mouse model for Down syndrome. Down syndrome is the most common neurodevelopmental disorder in humans and is caused by the presence of an extra copy of chromosome 21 (trisomy 21).

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9798357528452Subjects--Topical Terms:

767761
Stem cells.
Index Terms--Genre/Form:

542853
Electronic books.

Neuron-Specific Chromatin Remodeling in Social Behavior and Memory.
LDR:04959nmm a2200361K 4500 001 2354659
005 20230428105641.5
006 m o d
007 cr mn ---uuuuu
008 241011s2022 xx obm 000 0 eng d
020 $a 9798357528452
035 $a (MiAaPQ)AAI29755799
035 $a (MiAaPQ)STANFORDhm567kh7446
035 $a AAI29755799
040 $a MiAaPQ $b eng $c MiAaPQ $d NTU
100 1 $a Wenderski, Wendy Christine. $3 3695018
245 1 0 $a Neuron-Specific Chromatin Remodeling in Social Behavior and Memory.
264 0 $c 2022
300 $a 1 online resource (210 pages)
336 $a text $b txt $2 rdacontent
337 $a computer $b c $2 rdamedia
338 $a online resource $b cr $2 rdacarrier
500 $a Source: Dissertations Abstracts International, Volume: 84-05, Section: B.
500 $a Includes supplementary digital materials.
500 $a Advisor: Crabtree, Gerald.
502 $a Thesis (Ph.D.)--Stanford University, 2022.
504 $a Includes bibliographical references
520 $a Within the nucleus, DNA is packaged with histones and other proteins to form chromatin. This serves to protect and organize the genome, and to regulate processes like transcription. The BAF ATP-dependent chromatin remodeling complex controls the accessibility of DNA-and thus, transcription-by mobilizing histones and evicting Polycomb repressive complexes. Mutations in BAF subunits are enriched among individuals with neurodevelopmental disorders that feature intellectual disability and impaired social communication. Yet, how BAF mutations cause neurological symptoms, and more generally, how chromatin remodeling contributes to brain function, is poorly understood. This thesis work reveals BAF mechanisms in three neurodevelopmental disorders: autism, Down syndrome and Baraitser-Winter syndrome.Autism spectrum disorder (ASD) is a prevalent group of neurodevelopmental disorders that are defined by social deficits and restricted or repetitive behavior. Core BAF subunits including ARID1B are among the most frequently mutated genes in ASD, but the causal mechanisms are unknown. I hypothesized that BAF mutant ASD arises from impaired function of the neuronal BAF complex, which is defined by subunits ACTL6B, DPF1/3, and SS18L1. If true, mutations in neuronal-specific subunits would be expected to cause ASD. Whole exome sequencing revealed ACTL6B as the most significantly mutated gene in the Simons Recessive Autism Cohort, with loss-of-function mutations causing fully-penetrant Mendelian recessive ASD. Actl6b-/- mice on two genetic backgrounds exhibited patient-related social and memory impairments, stereotypies, hyperactivity, and corpus callosum hypogenesis, a clinical characteristic of BAF mutant ASD thought to arise from axonal targeting defects. I demonstrated a conserved role for ACTL6B in neural circuit formation by genetic complementation in fly olfactory projection neurons, where neurons expressing patient variants projected to the wrong glomerulus with 100% penetrance. These findings unveiled ACTL6B loss as a highly penetrant cause of Mendelian ASD, with conserved phenotypes in mouse and fly.Experiments using the Actl6b-/- mouse model have provided insight into molecular and cellular mechanisms. First, analysis of "resting state" gene expression and chromatin accessibility in network-silenced Actl6b-/- cortical neurons revealed signatures of activity like FOS expression, indicating a role for BAF in stabilizing resting state transcription. Second, genes involved in neurite targeting (e.g., semaphorins) and social behavior (e.g., serotonin receptor 1b; 5-HT1b) showed altered expression in Actl6b-/- neurons. Systemic administration of a 5-HT1b agonist fully rescued social impairments and hyperactivity in Actl6b-/- mice. Conditional deletion of the autism-related BAF subunit Arid1b in mouse serotonergic neurons caused social impairments that were rescued with the 5-HT1b agonist, indicating that serotonin-specific BAF chromatin remodeling is necessary for social behavior and facilitates pro-social neurotransmission. The 5-HT1b agonist rescued social behavior in 4 additional diverse mouse models for autism, indicating insufficient serotonin neurotransmission as a convergent and potentially causative mechanism for ASD.Through my studies of neuronal BAF, I identified the putative histone "reader" BRWD1 as a substoichiometric subunit and found that BRWD1 contributed to memory, transcriptional, and BAF targeting defects in a mouse model for Down syndrome. Down syndrome is the most common neurodevelopmental disorder in humans and is caused by the presence of an extra copy of chromosome 21 (trisomy 21).
533 $a Electronic reproduction. $b Ann Arbor, Mich. : $c ProQuest, $d 2023
538 $a Mode of access: World Wide Web
650 4 $a Stem cells. $3 767761
650 4 $a Mutation. $3 837917
650 4 $a Cognition & reasoning. $3 3556293
650 4 $a Cellular biology. $3 3172791
650 4 $a Cognitive psychology. $3 523881
650 4 $a Psychology. $3 519075
655 7 $a Electronic books. $2 lcsh $3 542853
690 $a 0379
690 $a 0633
690 $a 0621
710 2 $a ProQuest Information and Learning Co. $3 783688
710 2 $a Stanford University. $3 754827
773 0 $t Dissertations Abstracts International $g 84-05B.
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=29755799 $z click for full text (PQDT)