Correction: The intellectual disability gene Kirrel3 regulates target-specific mossy fiber synapse development in the hippocampus

Martin, E Anne; Muralidhar, Shruti; Wang, Zhirong; Cervantes, Diégo Cordero; Basu, Raunak; Taylor, Matthew R. G.; Hunter, Jennifer M.; Cutforth, Tyler; Wilke, Scott A.; Ghosh, Anirvan; Williams, Megan E.

doi:10.7554/elife.18706

Cited by 4 publications

(4 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…GWAS analyses revealed that CD34+CD133+ cells differentially affected AD protection in the genotypes of two genes (KIRREL3 and EXOC6B) (Figure 3; Tables 5 and 6). KIRREL3 as an adhesion molecule is found to play roles in morphology change and migration of muscle progenitor cells [57,58], and it is also involved in the differentiation of hematopoietic stem cells [59,60]. KIRREL3 has been shown to mediate neuron synapse formation and cell adhesion/guidance [61][62][63], as well as cell differentiation [57,58].…”

Section: Discussionmentioning

confidence: 99%

“…KIRREL3 as an adhesion molecule is found to play roles in morphology change and migration of muscle progenitor cells [57,58], and it is also involved in the differentiation of hematopoietic stem cells [59,60]. KIRREL3 has been shown to mediate neuron synapse formation and cell adhesion/guidance [61][62][63], as well as cell differentiation [57,58]. EXOC6B has the exocyst functions in the niche to promote germline stem cell (GSC) progeny differentiation in the Drosophila ovary by directly regulating EGFR membrane trafficking and signaling [64].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The association between circulating CD34+CD133+ endothelial progenitor cells and reduced risk of Alzheimer’s disease in the Framingham Heart Study

Wang,

Huang,

Ang

et al. 2024

Exploration of Medicine

View full text Add to dashboard Cite

Aim: Endothelial dysfunction has been associated with both cerebrovascular pathology and Alzheimer’s disease (AD). However, the connection between circulating endothelial cells and the risk of AD remains uncertain. The objective was to leverage data from the Framingham Heart Study to investigate various circulating endothelial subtypes and their potential correlations with the risk of AD. Methods: The study conducted data analyses using Cox proportional hazard regression and linear regression methods. Additionally, genome-wide association study (GWAS) was carried out to further explore the data. Results: Among the eleven distinct circulating endothelial subtypes, only circulating endothelial progenitor cells (EPCs) expressing CD34+CD133+ were found to be negatively and dose-dependently associated with reduced AD risk. This association persisted even after adjusting for age, sex, years of education, apolipoprotein E (APOE) ε4 status, and various vascular diseases. Particularly noteworthy was the significant association observed in individuals with hypertension and cerebral microbleeds. Consistently, positive associations were identified between CD34+CD133+ EPCs and specific brain regions, such as higher proportions of circulating CD34+CD133+ cells correlating with increased volumes of white matter and the hippocampus. Additionally, a GWAS study unveiled that CD34+CD133+ cells influenced AD risk specifically in individuals with homozygous genotypes for variants in two stem cell-related genes: kirre like nephrin family adhesion molecule 3 (KIRREL3, rs580382 CC and rs4144611 TT) and exocyst complex component 6B (EXOC6B, rs61619102 CC). Conclusions: The findings suggest that circulating CD34+CD133+ EPCs possess a protective effect and may offer a new therapeutic avenue for AD, especially in individuals with vascular pathology and those carrying specific genotypes of KIRREL3 and EXOC6B genes.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The association between circulating CD34+CD133+ endothelial progenitor cells and reduced risk of Alzheimer’s disease in the Framingham Heart Study

Wang,

Huang,

Ang

et al. 2024

Exploration of Medicine

View full text Add to dashboard Cite

show abstract

“…13,14 KIRREL3 has been shown to mediate neuron synapse formation and cell adhesion/guidance [34][35][36] , as well as cell differentiation. 37,38 The loss of KIRREL3 leads to changed axon organization, as well as male-male aggression and cognitive impairment, in mice. [39][40][41] Our data suggest that when brain KIRREL3 gene expression is low and vulnerable due to its genotypes or high methylation status, the impact of circulating CD34+CD133+ progenitor cells on decreasing AD risk is increased; in the counterpart genotypes, the KIRREL3 gene expression in the brain is high, and AD risk is not influenced by circulating endothelial CD34+CD133+ progenitor cells.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, both KIRREL3 16,35,38,[45][46][47][48][49][50] and EXOC6B [51][52][53] genes are related to ASD, another cognitive disease with a young age of onset. Like neurodegenerative diseases, ASD is also associated with cerebral hypoperfusion, 54 suggesting the presence of common cerebrovascular pathologies in both diseases.…”

Section: Discussionmentioning

confidence: 99%

Circulating Endothelial Progenitor Cells Reduce the Risk of Alzheimer’s Disease

Wang

Huang

Ang

et al. 2023

Preprint

View full text Add to dashboard Cite

Cerebrovascular damage coexists with Alzheimers disease (AD) pathology and increases AD risk. However, it is unclear whether endothelial progenitor cells reduce AD risk via cerebrovascular repair. By using the Framingham Heart Study (FHS) offspring cohort, which includes data on different progenitor cells, the incidence of AD dementia, peripheral and cerebrovascular pathologies, and genetic data (n = 1,566), we found that elevated numbers of circulating endothelial progenitor cells with CD34+CD133+ co-expressions had a dose-dependent association with decreased AD risk (HR = 0.67, 95% CI: 0.46-0.96, p = 0.03) after adjusting for age, sex, years of education, and APOE4. With stratification, this relationship was only significant among those individuals who had vascular pathologies, especially hypertension (HTN) and cerebral microbleeds (CMB), but not among those individuals who had neither peripheral nor central vascular pathologies. We applied a genome-wide association study (GWAS) and found that the number of CD34+CD133+ cells impacted AD risk depending on the homozygous genotypes of two genes: KIRREL3 rs580382 CC carriers (HR = 0.31, 95% CI: 0.17-0.57, p<0.001), KIRREL3 rs4144611 TT carriers (HR = 0.29, 95% CI: 0.15-0.57, p<0.001), and EXOC6B rs61619102 CC carriers (HR = 0.49, 95% CI: 0.31-0.75, p<0.001) after adjusting for confounders. In contrast, the relationship did not exist in their counterpart genotypes, e.g. KIRREL3 TT/CT or GG/GT carriers and EXOC6B GG/GC carriers. Our findings suggest that circulating CD34+CD133+ endothelial progenitor cells can be therapeutic in reducing AD risk in the presence of cerebrovascular pathology, especially in KIRREL3 and EXOC6B genotype carriers.

show abstract

Cellular and molecular characterization of multiplex autism in human induced pluripotent stem cell-derived neurons

Lewis¹,

Meganathan²,

Baldridge³

et al. 2019

Preprint

View full text Add to dashboard Cite

20Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with 21 pronounced heritability in the general population. This is largely attributable to effects of 22 polygenic susceptibility, with inherited liability exhibiting distinct sex differences in phenotypic 23expression. Attempts to model ASD in human cellular systems have principally involved rare de 24 novo mutations associated with ASD phenocopies. However, by definition, these models are not 25 representative of polygenic liability, which accounts for the vast share of population-attributable 26 risk. 27Methods: Here, we performed what is, to our knowledge, the first attempt to model multiplex 28 autism using patient-derived induced pluripotent stem cells (iPSCs) in a family manifesting 29 incremental degrees of phenotypic expression of inherited liability (absent, intermediate, 30 severe). The family members share an inherited variant of unknown significance in GPD2, a 31 gene that was previously associated with developmental disability but here is insufficient by 32 itself to cause ASD. iPSCs from three first-degree relatives and an unrelated control were 33 differentiated into both cortical excitatory (cExN) and cortical inhibitory (cIN) neurons, and 34 cellular phenotyping and transcriptomic analysis were conducted. 35 Results: cExN neurospheres from the two affected individuals were reduced in size, compared 36 to those derived from unaffected related and unrelated individuals. This reduction was, at least 37 in part, due to increased apoptosis of cells from affected individuals upon initiation of cExN 38 neural induction. Likewise, cIN neural progenitor cells from affected individuals exhibited 39 increased apoptosis, compared to both unaffected individuals. Transcriptomic analysis of both 40 cExN and cIN neural progenitor cells revealed distinct molecular signatures associated with 41 affectation, including misregulation of suites of genes associated with neural development, 42 neuronal function, and behavior, as well as altered expression of ASD risk-associated genes. 43 3 Conclusions:We have provided evidence of morphological, physiological, and transcriptomic 44 signatures of polygenic liability to ASD from an analysis of cellular models derived from a 45 multiplex autism family. ASD is commonly inherited on the basis of additive genetic liability. 46Therefore, identifying convergent cellular and molecular phenotypes resulting from polygenic 47 and monogenic susceptibility may provide a critical bridge for determining which of the disparate 48 effects of rare highly deleterious mutations might also apply to common autistic syndromes. 49 spectrum disorder (ASD) is a neurodevelopmental disorder with a complex and poorly 65 understood etiology (1-3). Behavioral and imaging studies have been valuable for defining 66 deficits in affected individuals and characterizing alterations at the level of the brain. However, 67 we are extremely limited in our ability to acquire or experimentally manipulate human brain 68 tissue from l...

show abstract

Correction: The intellectual disability gene Kirrel3 regulates target-specific mossy fiber synapse development in the hippocampus

Cited by 4 publications

References 0 publications

The association between circulating CD34+CD133+ endothelial progenitor cells and reduced risk of Alzheimer’s disease in the Framingham Heart Study

The association between circulating CD34+CD133+ endothelial progenitor cells and reduced risk of Alzheimer’s disease in the Framingham Heart Study

Circulating Endothelial Progenitor Cells Reduce the Risk of Alzheimer’s Disease

Cellular and molecular characterization of multiplex autism in human induced pluripotent stem cell-derived neurons

Contact Info

Product

Resources

About