The role of Pax6 in brain development and its impact on pathogenesis of autism spectrum disorder

Kikkawa, Takako; Casingal, Cristine R.; Chun, Seung Hee; Shinohara, Hiroshi; Hiraoka, Kotaro; Osumi, Noriko

doi:10.1016/j.brainres.2018.02.041

Cited by 40 publications

(38 citation statements)

References 147 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…PAX6 and PAX8 are members of the paired box (PAX) family of transcription factors. While PAX 6 is involved in modulating the fate of neural progenitor cells [ 37 ], genetic variants in PAX8 are associated with sleep disturbance [ 38 , 39 ], a frequent comorbidity of ASD. SHANK1 is a scaffolding protein at the postsynaptic density that has been found to be involved in ASD [ 40 ].…”

Section: Resultsmentioning

confidence: 99%

Phenotypic Subtyping and Re-Analysis of Existing Methylation Data from Autistic Probands in Simplex Families Reveal ASD Subtype-Associated Differentially Methylated Genes and Biological Functions

Lee

2020

IJMS

View full text Add to dashboard Cite

Autism spectrum disorder (ASD) describes a group of neurodevelopmental disorders with core deficits in social communication and manifestation of restricted, repetitive, and stereotyped behaviors. Despite the core symptomatology, ASD is extremely heterogeneous with respect to the severity of symptoms and behaviors. This heterogeneity presents an inherent challenge to all large-scale genome-wide omics analyses. In the present study, we address this heterogeneity by stratifying ASD probands from simplex families according to the severity of behavioral scores on the Autism Diagnostic Interview-Revised diagnostic instrument, followed by re-analysis of existing DNA methylation data from individuals in three ASD subphenotypes in comparison to that of their respective unaffected siblings. We demonstrate that subphenotyping of cases enables the identification of over 1.6 times the number of statistically significant differentially methylated regions (DMR) and DMR-associated genes (DAGs) between cases and controls, compared to that identified when all cases are combined. Our analyses also reveal ASD-related neurological functions and comorbidities that are enriched among DAGs in each phenotypic subgroup but not in the combined case group. Moreover, relational gene networks constructed with the DAGs reveal signaling pathways associated with specific functions and comorbidities. In addition, a network comprised of DAGs shared among all ASD subgroups and the combined case group is enriched in genes involved in inflammatory responses, suggesting that neuroinflammation may be a common theme underlying core features of ASD. These findings demonstrate the value of phenotype definition in methylomic analyses of ASD and may aid in the development of subtype-directed diagnostics and therapeutics.

show abstract

Section: Resultsmentioning

confidence: 99%

Phenotypic Subtyping and Re-Analysis of Existing Methylation Data from Autistic Probands in Simplex Families Reveal ASD Subtype-Associated Differentially Methylated Genes and Biological Functions

Lee

2020

IJMS

View full text Add to dashboard Cite

show abstract

“…SLC1A2, encoding a glutamate transporter, and PRRG4, encoding a vitamin K-dependent membrane protein, are also located in 11p13-p12, a region that is identified by linkage analysis as an autism candidate region [130]. However, PAX6 itself should also be considered, since some patients with PAX6 intragenic mutations present with cerebral abnormalities as well as development delays and autism [16,17,131].…”

Section: Wagr (Mim 194072)mentioning

confidence: 99%

“…Other ocular phenotypes include microphthalmia, optic nerve anomalies, or anterior segment dysgenesis [15]. Systemic features can include neurodevelopmental abnormalities, like autism and attention deficit hyperactivity (ADHD) disorders, language impairment [16][17][18], and in some cases the absence or malformations of the pineal and pituitary gland [19][20][21][22]. Defects in PAX6 have also been associated with obesity and diabetes mellitus due to its role in pancreas development [23,24].…”

Section: Introductionmentioning

confidence: 99%

The Spectrum of PAX6 Mutations and Genotype-Phenotype Correlations in the Eye

Cunha¹,

Arno

Cortón

et al. 2019

Genes

119

107

View full text Add to dashboard Cite

The transcription factor PAX6 is essential in ocular development in vertebrates, being considered the master regulator of the eye. During eye development, it is essential for the correct patterning and formation of the multi-layered optic cup and it is involved in the developing lens and corneal epithelium. In adulthood, it is mostly expressed in cornea, iris, and lens. PAX6 is a dosage-sensitive gene and it is highly regulated by several elements located upstream, downstream, and within the gene. There are more than 500 different mutations described to affect PAX6 and its regulatory regions, the majority of which lead to PAX6 haploinsufficiency, causing several ocular and systemic abnormalities. Aniridia is an autosomal dominant disorder that is marked by the complete or partial absence of the iris, foveal hypoplasia, and nystagmus, and is caused by heterozygous PAX6 mutations. Other ocular abnormalities have also been associated with PAX6 changes, and genotype-phenotype correlations are emerging. This review will cover recent advancements in PAX6 regulation, particularly the role of several enhancers that are known to regulate PAX6 during eye development and disease. We will also present an updated overview of the mutation spectrum, where an increasing number of mutations in the non-coding regions have been reported. Novel genotype-phenotype correlations will also be discussed.

show abstract

“…The largest number of mRNA targets we found are genes whose products are classified into "transcription regulation" that controls the proliferation of neural stem cells and their transition to differentiating neural progenitors (Lee et al, 2014). One of the FMRP target in this category is Pax6, a key transcription factor in brain development by regulating hundreds of genes related to ASD (see review by Kikkawa et al, 2019). The mRNA and protein expression of Pax6 in the Fmr1-KO mice showed a decreased tendency at below the significant level ( Figure S2).…”

Section: Discussionmentioning

confidence: 99%

Identification of FMRP target genes expressed in corticogenesis: implication for common phenotypes among neurodevelopmental disorders

Casingal

Kikkawa

Inada

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Keywords: FMRP, FXS, mRNA targets, corticogenesis al., 2014). Postnatally, FMRP is localized in the cell body, proximal dendrites and axons of neurons (Darnell et al., 2011;Castrén, 2016), and plays profound regulatory roles in the synaptic function and neuronal plasticity (Bassell and Warren, 2008; De Rubeis and Bagni, 2010) through interaction with transcripts that encode pre-and postsynaptic proteins, and also regulation of mRNA trafficking into dendrites (Abrahams and Geschwind, 2008;Bassell and Warren, 2008;Abrahams et al., 2013).Altogether, FMRP has multifunctional roles at distinct times in brain development.Since the discovery of FMRP, a large effort has been made to characterize targets of FMRP using several methods including RNA immunoprecipitation (RIP) Protein-protein association networkTo predict biological functions, pathways, and protein-protein interactions, 124 proteins encoded by both FMRP targets and ASD-associated genes were analyzed using the STRING Database (Szklarczyk et al., 2017). Four statistically significant functional clusters were selected and highlighted (FDR<0.05; Figure 3). The cluster with the largest number of FMRP targets/ASD-associated genes was categorized as "transcription regulation" comprised of 28 genes, i.e.,

show abstract

The role of Pax6 in brain development and its impact on pathogenesis of autism spectrum disorder

Cited by 40 publications

References 147 publications

Phenotypic Subtyping and Re-Analysis of Existing Methylation Data from Autistic Probands in Simplex Families Reveal ASD Subtype-Associated Differentially Methylated Genes and Biological Functions

Phenotypic Subtyping and Re-Analysis of Existing Methylation Data from Autistic Probands in Simplex Families Reveal ASD Subtype-Associated Differentially Methylated Genes and Biological Functions

The Spectrum of PAX6 Mutations and Genotype-Phenotype Correlations in the Eye

Identification of FMRP target genes expressed in corticogenesis: implication for common phenotypes among neurodevelopmental disorders

Contact Info

Product

Resources

About