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Gamma-Protocadherin Cis- and Trans -...

Molumby, Michael Jacob.

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Gamma-Protocadherin Cis- and Trans -Interactions Regulate the Development of Dendrite Arbors and Synapses in the Cerebral Cortex.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Gamma-Protocadherin Cis- and Trans -Interactions Regulate the Development of Dendrite Arbors and Synapses in the Cerebral Cortex./
Author:	Molumby, Michael Jacob.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2017,
Description:	161 p.
Notes:	Source: Dissertation Abstracts International, Volume: 79-02(E), Section: B.
Contained By:	Dissertation Abstracts International79-02B(E).
Subject:	Neurosciences. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10599757
ISBN:	9780355244496

Gamma-Protocadherin Cis- and Trans -Interactions Regulate the Development of Dendrite Arbors and Synapses in the Cerebral Cortex.
Molumby, Michael Jacob.

Gamma-Protocadherin Cis- and Trans -Interactions Regulate the Development of Dendrite Arbors and Synapses in the Cerebral Cortex. - Ann Arbor : ProQuest Dissertations & Theses, 2017 - 161 p.

Source: Dissertation Abstracts International, Volume: 79-02(E), Section: B.

Thesis (Ph.D.)--The University of Iowa, 2017.

The alpha-, beta-, and gamma--Protocadherins (gamma-Pcdhs) are cadherin superfamily adhesion molecules encoded by clustered gene families. The 22 gamma-Pcdhs are combinatorially expressed in the central nervous system (CNS) by neurons and astrocytes, and play critical roles in synaptogenesis, dendrite arborization, and the survival of subsets of neurons. The gamma-Pcdhs promiscuously form cis-multimers that interact strictly homophilically in trans (Molumby et al., 2016; Schreiner and Weiner, 2010); the alpha- and beta-Pcdhs were subsequently shown to interact in a similar homophilic manner (Rubinstein et al., 2015; Thu et al., 2014). The Pcdh gene clusters thus have the potential to generate millions of distinct adhesive interfaces, providing CNS cells with molecular identities that shape neuronal morphology.

ISBN: 9780355244496Subjects--Topical Terms:

588700
Neurosciences.

Gamma-Protocadherin Cis- and Trans -Interactions Regulate the Development of Dendrite Arbors and Synapses in the Cerebral Cortex.
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100 1 $a Molumby, Michael Jacob. $3 3347295
245 1 0 $a Gamma-Protocadherin Cis- and Trans -Interactions Regulate the Development of Dendrite Arbors and Synapses in the Cerebral Cortex.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2017
300 $a 161 p.
500 $a Source: Dissertation Abstracts International, Volume: 79-02(E), Section: B.
500 $a Adviser: Joshua A. Weiner.
502 $a Thesis (Ph.D.)--The University of Iowa, 2017.
520 $a The alpha-, beta-, and gamma--Protocadherins (gamma-Pcdhs) are cadherin superfamily adhesion molecules encoded by clustered gene families. The 22 gamma-Pcdhs are combinatorially expressed in the central nervous system (CNS) by neurons and astrocytes, and play critical roles in synaptogenesis, dendrite arborization, and the survival of subsets of neurons. The gamma-Pcdhs promiscuously form cis-multimers that interact strictly homophilically in trans (Molumby et al., 2016; Schreiner and Weiner, 2010); the alpha- and beta-Pcdhs were subsequently shown to interact in a similar homophilic manner (Rubinstein et al., 2015; Thu et al., 2014). The Pcdh gene clusters thus have the potential to generate millions of distinct adhesive interfaces, providing CNS cells with molecular identities that shape neuronal morphology.
520 $a We demonstrated previously that, in mice lacking the gamma-Pcdhs in the cerebral cortex, pyramidal neurons exhibit severely reduced dendrite arborization (Garrett et al., 2012a). This, combined with many studies of gamma-Pcdh interactions in vitro, suggests that homophilic, adhesive gamma-Pcdh interactions between neurons, and between neurons and glia, provide a positive signal for dendrite growth. However, in retinal starburst amacrine cells and cerebellar Purkinje cells, loss of the gamma-Pcdhs resulted in aberrant dendrite fasciculation and self-crossing (Lefebvre et al., 2012), suggesting that these molecules can mediate repulsive self-avoidance between a neuron's own dendrites.
520 $a In Chapter I of this thesis I utilized transgenic mice to manipulate expression in vivo, to show that the complexity of a cortical neuron's dendritic arbor is determined by homophilic gamma-Pcdh isoform matching with other cells. Expression of the same single isoform in a neuron can result in either exuberant, or minimal, dendrite complexity depending on whether surrounding cells express the same isoform. Additionally, loss of gamma-Pcdh in astrocytes, or induced astrocyte-neuron mis-matching, reduces dendrite complexity cell non-autonomously. This indicates a neuron's pattern of connectivity is indeed regulated by specific interactions between cells that are distinct from the repulsive self-avoidance seen in isoneuronal processes of planar cell types.
520 $a In addition to modulating dendrite branch development, the gamma-Pcdhs have been shown to regulate the progression of spinal cord synaptogenesis (Garrett and Weiner, 2009). A role for these molecules in cortical dendritic spines and synapses, however, had yet not been examined. In Chapter II of this thesis, I provide evidence that the gamma-Pcdhs negatively regulate synapse formation and spine morphogenesis in forebrain neurons. Mice lacking all gamma-Pcdhs in the cortex exhibit significantly increased spine and synapse density in vivo, while spine density is significantly decreased in mice overexpressing one of the 22 gamma-Pcdh isoforms. To explain this functional result, we present in vitro evidence to show that gamma-Pcdhs physically and functionally interact with the synaptic cell adhesion molecule neuroligin-1. This work suggests a potential new mechanism by which gamma-Pcdhs regulate the "choice" between dendrite arbor growth and formation and/or stabilization of dendritic spines and synapses in the developing brain.
520 $a Given that disruptions in the pattern and density of dendritic arbors and spines are a hallmark of neurodevelopmental disorders such as autism and Down, Rett, and fragile X syndromes, my work may provide the basic science foundation for future therapeutic approaches focused on Pcdhs and their associated signaling pathways.
590 $a School code: 0096.
650 4 $a Neurosciences. $3 588700
650 4 $a Developmental biology. $3 592588
650 4 $a Genetics. $3 530508
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690 $a 0758
690 $a 0369
710 2 $a The University of Iowa. $b Biology. $3 3181866
773 0 $t Dissertation Abstracts International $g 79-02B(E).
790 $a 0096
791 $a Ph.D.
792 $a 2017
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10599757