The gamma-Protocadherins regulate the survival of GABAergic interneurons during developmentally-regulated cell death

Carriere, Candace H.; Sing, Anson; Wang, Wendy Xueyi; Jones, Brian E.; Yee, Yohan; Ellegood, Jacob; Marocha, Julie; Maganti, Harinad; Awofala, Lola; Aziz, Amar; Lerch, Jason P.; Lefebvre, Julie L.

doi:10.1101/2020.01.15.908087

Cited by 6 publications

(11 citation statements)

References 129 publications

(173 reference statements)

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“…Consistently, layer 1 RLN+ cells, which are largely derived from the CGE ( Miyoshi et al, 2010 ), were not affected by Pcdhg loss of function, but RNL cells in deeper layers 2–6 (many of which are MGE-derived and also positive for SST) showed reduced numbers ( Figure 3—figure supplement 2 ). Interestingly, we observed that in our Nkx2.1 Cre ; Ai14 ;Pcdhg fcon3/fcon3 mice, the number of un-recombined PV and SST (PV+/tdTomato- and SST+/tdTomato-) cells was significantly increased compared to WT mice ( Figure 3—figure supplement 4 ), a result consistent with recent observations ( Carriere et al, 2020 ). PV+/tdTomato- and SST+/tdTomato- cells are likely derived from the most dorsal MGE at the interface with LGE expressing NKX6.2 in a region of low, or no expression of NKX2.1 ( Hu et al, 2017a ; Hu et al, 2017b ; Fogarty et al, 2007 ; Sousa et al, 2009 ).…”

Section: Resultssupporting

confidence: 92%

Clustered gamma-protocadherins regulate cortical interneuron programmed cell death

Leon

Spatazza

Rakela

et al. 2020

eLife

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Cortical function critically depends on inhibitory/excitatory balance. Cortical inhibitory interneurons (cINs) are born in the ventral forebrain and migrate into cortex, where their numbers are adjusted by programmed cell death. Here we show that loss of clustered gamma protocadherins (Pcdhg), but not of genes in the alpha or beta clusters, increased dramatically cIN BAX-dependent cell death in mice. Surprisingly, electrophysiological and morphological properties of Pcdhg-deficient and wild-type cINs during the period of cIN cell death were indistinguishable. Co-transplantation of wild-type with Pcdhg-deficient interneuron precursors further reduced mutant cIN survival, but the proportion of mutant and wild-type cells undergoing cell death was not affected by their density. Transplantation also allowed us to test for the contribution of Pcdhg isoforms to the regulation of cIN cell death. We conclude that Pcdhg, specifically Pcdhgc3, Pcdhgc4, and Pcdhgc5, play a critical role in regulating cIN survival during the endogenous period of programmed cIN death.

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Section: Resultssupporting

confidence: 92%

Clustered gamma-protocadherins regulate cortical interneuron programmed cell death

Leon

Spatazza

Rakela

et al. 2020

eLife

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“…As discussed above, Pyk2 and FAK could interconnect three different Pcdh-modulated signaling pathways. Recently the PI3K-AKT pathway was shown to be involved in Pcdh-mediated neuronal survival (Carriere et al, 2020). The interplay between this pathway and Pyk2 was demonstrated in several cancer types (reviewed in Shen and Guo, 2018).…”

Section: Resultsmentioning

confidence: 99%

“…Numerous anti-apoptotic/pro-survival actions have been attributed to the PI3K-AKT pathway (Brunet et al, 2001), and cytoplasmic phospho-AKT is known to act as an anti-apoptotic factor. As loss of γ-Pcdhs increased apoptosis in cINs, γ-Pcdhs appear to have a role in cIN survival mediated by AKT (Carriere et al, 2020).…”

Section: Dosage Of Pcdhs In Relation To Apoptosis In the Brainmentioning

confidence: 98%

“…Members of the γ-Pcdh cluster are known to prevent neuronal apoptosis of spinal cord interneurons, retinal cells, and cortical interneurons (cINs) ( Wang et al, 2002b ; Lefebvre et al, 2008 ; Prasad et al, 2008 ; Chen W. V. et al, 2012 ; Garrett et al, 2012 ; Hasegawa et al, 2016 , 2017 ; Carriere et al, 2020 ; Leon et al, 2020 ). Transplantation studies and knockout mice phenotyping showed that loss of C-type γ-Pcdhs leads to increased cell death in spinal cord interneurons and cINs ( Chen W. V. et al, 2012 ; Leon et al, 2020 ).…”

Section: Expression and Roles Of Pcdhsmentioning

confidence: 99%

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Protocadherins at the Crossroad of Signaling Pathways

Pancho

Aerts

Mitsogiannis

et al. 2020

Front. Mol. Neurosci.

109

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Protocadherins (Pcdhs) are cell adhesion molecules that belong to the cadherin superfamily, and are subdivided into clustered (cPcdhs) and non-clustered Pcdhs (ncPcdhs) in vertebrates. In this review, we summarize their discovery, expression mechanisms, and roles in neuronal development and cancer, thereby highlighting the context-dependent nature of their actions. We furthermore provide an extensive overview of current structural knowledge, and its implications concerning extracellular interactions between cPcdhs, ncPcdhs, and classical cadherins. Next, we survey the known molecular action mechanisms of Pcdhs, emphasizing the regulatory functions of proteolytic processing and domain shedding. In addition, we outline the importance of Pcdh intracellular domains in the regulation of downstream signaling cascades, and we describe putative Pcdh interactions with intracellular molecules including components of the WAVE complex, the Wnt pathway, and apoptotic cascades. Our overview combines molecular interaction data from different contexts, such as neural development and cancer. This comprehensive approach reveals potential common Pcdh signaling hubs, and points out future directions for research. Functional studies of such key factors within the context of neural development might yield innovative insights into the molecular etiology of Pcdh-related neurodevelopmental disorders.

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“…Detailed methods are described in the Supplementary Methods; these data processing and spatial enrichment methods have been previously used elsewhere, both in exploratory methods, 39,40 and to support targeted hypotheses. 41…”

Section: Spatial Gene Expression Analysismentioning

confidence: 99%

Characterization of Mice Bearing Humanized Androgen Receptor Genes (h/mAr) Varying in Polymorphism Length

Lindenmaier

Yee

Kinman

et al. 2020

Preprint

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The androgen receptor (AR) is known for masculinization of behavior and brain. To better understand the role that AR plays, mice bearing humanized Ar genes with varying lengths of a polymorphic N-terminal glutamine (Q) tract were created (Albertelli et al 2006). The length of the Q tract is inversely proporitional to AR activity. Biological studies of the Q tract length may also provide a window into potential AR contributions to sex-biases in disease risk. Here we take a multi-pronged approach to characterizing AR signaling effects on brain and behavior in mice using the humanized Ar Q tract model. We first map effects of Q tract length on regional brain anatomy, and consider if these are modified by gonadal sex. We then test the notion that spatial patterns of anatomical variation related to Q tract length could be organized by intrinsic spatiotemporal patterning of AR gene expression in the mouse brain. Finally, we test influences of Q tract length on four behavioral tests. Altering Q tract length led to neuroanatomical differences in a non-linear dosage-dependent fashion. Gene expression analyses indicated that adult neuroanatomical changes due to Q tract length are only associated with neurodevelopment (as opposed to adulthood). No significant effect of Q tract length was found on the behavior of the three mouse models. These results indicate that AR activity differentially mediates neuroanatomy and behavior, that AR activity alone does not mediate sex differences, and that neurodevelopmental processes are associated with spatial patterns of volume changes due to Q tract length in adulthood. They also indicate that androgen sensitivity in adulthood does not directly lead to autism-related behaviors or neuroanatomy, although neurodevelopmental processes may play a role earlier. Further study into sex differences, development, other behaviors, and other sex-specific mechanisms are needed to better understand AR sensitivity, neurodevelopmental disorders, and the sex difference in their prevalence

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The gamma-Protocadherins regulate the survival of GABAergic interneurons during developmentally-regulated cell death

Cited by 6 publications

References 129 publications

Clustered gamma-protocadherins regulate cortical interneuron programmed cell death

Clustered gamma-protocadherins regulate cortical interneuron programmed cell death

Protocadherins at the Crossroad of Signaling Pathways

Characterization of Mice Bearing Humanized Androgen Receptor Genes (h/mAr) Varying in Polymorphism Length

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