Psychosis Risk Candidate ZNF804A Localizes to Synapses and Regulates Neurite Formation and Dendritic Spine Structure

Deans, P.J. Michael; Raval, Pooja; Sellers, Katherine J.; Gatford, Nicholas J.F.; Halai, Sanjay; Duarte, Rodrigo R.R.; Shum, Carole; Warre-Cornish, Katherine; Kaplun, Victoria E.; Cocks, Graham; Hill, Matthew; Bray, Nicholas John; Price, John; Srivastava, Deepak P.

doi:10.1016/j.biopsych.2016.08.038

Cited by 87 publications

(106 citation statements)

References 42 publications

(97 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Keratinocytes were extracted from hair follicles from the participants, and reprogrammed into iPSCs using the Yamanaka factors 35 . As autism is known to affect several regions of the cerebral cortex [5][6][7][8] , the iPSC lines were differentiated into neural cells of a cortical lineage using a previously described method 25,27 . Three developmental stages were specifically studied ( Figure 1A): (1) Day 8: early neural precursors, (2) Day 21: late neural precursors, (3) Day 35: cortical neural cells.…”

Section: Cortical Differentiation In Autism Ipsc Lines Diverge From Tmentioning

confidence: 99%

“…We differentiated iPSC lines into cortical neurons using a well-established method based on dual SMAD inhibition; this results in the recapitulation of key hallmarks of corticogenesis and the generation of cortical neurons 25,27 . iPSCs were differentiated till early neuron stageday 35 ( Figure 1A) (see extended experimental procedures).…”

Section: Neuronal Differentiationmentioning

confidence: 99%

See 1 more Smart Citation

Atypical neurogenesis in induced pluripotent stem cell (iPSC) from autistic individuals

Adhya

Swarup

Nagy

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

30Autism is a heterogenous collection of disorders with a complex molecular underpinning. 31Evidence from post mortem studies using adult brains have identified atypical co-expression 32 of genes which may occur during the prenatal period. Recent studies using induced pluripotent 33 stem cells (iPSCs) generated from autistic individuals have suggested that prenatal 34 development is a critical period for the emergence of pathophysiology associated with this 35 condition. However, how early during development these differences emerge and whether such 36 alterations can be seen across the development of multiple brain regions is unclear. In this study 37 we investigated whether early prenatal stages of neurodevelopment differ between iPSCs 38 generated from typically developing and autistic individuals. We specifically selected autistic 39 individuals unrelated to each other with a heterogeneous genetic background and no known 40 comorbidities, to probe for common molecular phenotypes. Differentiation of iPSCs towards a 41 cortical lineage revealed abnormal cell fate acquisition from an early stage of development. 42Interestingly, abnormal differentiation occurred in the absence of alteration in cell proliferation 43 during cortical differentiation, differing from previous studies. Moreover, these effects 44 appeared specific for the acquisition of a cortical fate, as differentiation of iPSCs towards a 45 midbrain lineage was not accompanied by differences in neurogenesis between typically 46 developing and autism iPSC lines. RNA-sequencing on a subset of our cohort further revealed 47 autism-specific signatures during cortical differentiation similar to that observed in post 48 mortem studies, indicating a potential common biological mechanism. Together, these data 49 suggest unique developmental differences associated with autism may establish at an early 50 prenatal stage. 51 52 53 4 54 Recent methodological advances in the field of induced pluripotent stem cell (iPSC) 75technology [15][16][17][18][19][20] has made it possible to study prenatal cellular behaviour in autism in detail, 76 something that was not possible using post mortem brains. IPSCs have similar abilities to 77 5 embryonic stem cells to generate any tissue of the body. These can then be differentiated into 78 neurons of various lineages 15-17, 19, 20 . As the neurons contain the same genetic information as 79 the individual from whom it was derived, typical or autistic, its cellular behaviours is 80 influenced by its genetic background. Using these methods, studies have shown significant 81 anomalies in cellular/molecular behaviour during prenatal-equivalent periods of development 82 in autistic individuals [21][22][23] . One such study generated iPSCs from autistic individuals who were 83 comorbid for macrocephaly, and demonstrated: (1) atypical cortical differentiation and 84 increased cell proliferation of cortical neural precursor cells (NPCs) from iPSCs, and (2) an 85 imbalance in excitatory (glutamate-producing) and inhibitory (GABA-produ...

show abstract

Section: Cortical Differentiation In Autism Ipsc Lines Diverge From Tmentioning

confidence: 99%

Section: Neuronal Differentiationmentioning

confidence: 99%

Atypical neurogenesis in induced pluripotent stem cell (iPSC) from autistic individuals

Adhya

Swarup

Nagy

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…The similarity in effect and signaling pathways activated by these proteins is consistent with the comparatively high amino acid sequence homology between NLGN3 and NLGN4X (69.026% homology) 38 , 39 and the finding that NLGN4 evolved rapidly from other NLGN gene sequences in mice 40 . Additionally, NLGN4X overexpression was recently found to rescue aberrant neurite outgrowth induced by ZNF804A knockdown 41 . Combined, these suggest necessary roles for both proteins in mammalian neuritogenesis as well as a degree of functional overlap between NLGN3 and NLGN4X.…”

Section: Discussionmentioning

confidence: 99%

Nanoscopic Clustering of Neuroligin-3 and Neuroligin-4X Regulates Growth Cone Organization and Size

Gatford¹,

Deans

Duarte³

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

The cell-adhesion proteins neuroligin-3 and neuroligin-4X (NLGN3/4X) have well described roles in synapse formation. NLGN3/4X are also expressed highly during neurodevelopment. However, the role these proteins play during this period is unknown. Here we show that NLGN3/4X localized to the leading edge of growth cones where itpromoted neuritogenesis in immature human neurons. Super-resolution microscopyrevealed that NLGN3/4X clustering induced growth cone enlargement and influenced actin filament organization. Critically, these morphological effects were not induced by Autism spectrum condition (ASC)-associated NLGN3/4X variants. Finally, actin regulators p21-activated kinase 1 (PAK1) and cofilin were found to be activated by NLGN3/4X and involved in mediating the effects of these adhesion proteins on actin filaments, growth cones, and neuritogenesis. These data reveal a novel role for NLGN3 and NLGN4X in the development of neuronal architecture, which may be altered in the presence of ASD-associated variants.

show abstract

“…In addition, our post-mortem and in vitro work suggest HERV expression is important in the DLPFC and during its development, but we still do not know the function of these HERVs. To infer function we performed WGCNA which provides insight into which processes risk HERVs moderate, but future functional studies are required to definitively characterize how HERVs, particularly ERVLE_8q24.3h and LTR25_6q21, influence the transcriptome, neural stem cell proliferation or neuronal differentiation in the context of schizophrenia risk, as is currently being investigated in relation to protein-coding risk genes 32,33,47,48 .…”

Section: Discussionmentioning

confidence: 99%

Schizophrenia risk from locus-specific human endogenous retroviruses

Duarte

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

24Schizophrenia genome-wide association studies highlight the substantial contribution of risk 25 attributed to the non-coding genome where human endogenous retroviruses (HERVs) are encoded. 26These ancient viral elements have previously been overlooked in genetic and transcriptomic studies 27 due to their poor annotation and repetitive nature. Using a new, comprehensive HERV annotation, 28 we found that the fraction of the genome where HERVs are located (the 'retrogenome') is enriched 29 for schizophrenia risk variants, and that there are 148 disparate HERVs involved in susceptibility. 30Analysis of RNA-sequencing data from the dorsolateral prefrontal cortex of 259 schizophrenia cases 31 and 279 controls from the CommonMind Consortium showed that HERVs are actively expressed in 32 the brain (n = 3,979), regulated in cis by common genetic variants (n = 1,759), and differentially 33 expressed in patients (n = 81). Convergent analyses implicate LTR25_6q21 and ERVLE_8q24.3h 34 as HERVs of etiological relevance to schizophrenia, which are co-regulated with genes involved in 35 neuronal and mitochondrial function, respectively. Our findings provide a strong rationale for 36 exploring the retrogenome and the expression of these locus-specific HERVs as novel risk factors 37 for schizophrenia and potential diagnostic biomarkers and treatment targets. 39 42These viruses multiplied through a copy-and-paste mechanism and were eventually endogenized 43 (i.e., vertically transmitted), and now constitute approximately 8% of the genome 1,2 . These repetitive 44 sequences were generally assumed to be transcriptionally inactive in the modern genome, having a 45 purely regulatory function due to the retainment of the viral promoters (long-terminal repeats, LTRs). 46However, certain HERVs were co-opted to serve novel specialized roles, including in the regulation 47 of embryonic development 3,4 and neural progenitor cells 5,6 . They have also been implicated in 48 neuropsychiatric conditions such as amyotrophic lateral sclerosis 7-9 , major depressive disorder, 49 bipolar disorder, and schizophrenia 10-12 . Despite their abundance in the genome and relevance to 50 disease and fundamental aspects of human biology, the location and function of most HERVs remain 51 elusive to-date. 53Recent large genome-wide association studies (GWAS) comparing schizophrenia cases and non-54 affected individuals enabled the identification of polymorphisms mediating risk for this disorder [13][14][15] . 55These studies highlight the substantial contribution of risk attributed to the non-coding genome, 56where HERVs are encoded, which are often overlooked in both genomic and transcriptomic 57 studies 16 . Until recently, there was no comprehensively annotated map of HERVs in the genome, 58 and there were no computationally efficient tools to analyze the expression of these repetitive 59 sequences with single-locus resolution. Consequently, previous studies were unable to test whether 60 locus-specific HERVs were genetically associated with traits of int...

show abstract

Psychosis Risk Candidate ZNF804A Localizes to Synapses and Regulates Neurite Formation and Dendritic Spine Structure

Cited by 87 publications

References 42 publications

Atypical neurogenesis in induced pluripotent stem cell (iPSC) from autistic individuals

Atypical neurogenesis in induced pluripotent stem cell (iPSC) from autistic individuals

Nanoscopic Clustering of Neuroligin-3 and Neuroligin-4X Regulates Growth Cone Organization and Size

Schizophrenia risk from locus-specific human endogenous retroviruses

Contact Info

Product

Resources

About