Biology subjects

Liaw, E.

Publications and source records attributed to Liaw, E..

3 recordsLinked to original sources

bioRxiv2025

The Association Between SLIT2 in Human Vitreous Humor and Plasma and Neurocognitive Test Scores

BackgroundSlit Guidance Ligand 2 (SLIT2) binds Roundabout (ROBO) guidance receptors to direct axon pathfinding and neuron migration during nervous system development. SLIT2 expression has previously been linked to dementia risk. ObjectiveTo study the association between SLIT2 expression in human vitreous humor and plasma samples and neurocognitive test scores in a cross-sectional cohort study utilizing a novel, highly-sensitive Meso Scale Discovery (MSD) assay for SLIT2 detection. MethodsSeventy-nine individuals with a mean age of 55.79 {+/-} 12.03 years underwent eye surgery with collection of vitreous humor, blood (plasma) collection, and neurocognitive assessment. Vitreous humor and plasma samples were analyzed by SLIT2 MSD electrochemiluminescence immunoassay. Associations between SLIT2 levels in vitreous humor and plasma were analyzed using GraphPad Prism. ResultsWe found up to a 7-fold higher level of SLIT2 in human vitreous humor compared to plasma. Lower vitreous SLIT2 levels were associated with a lower Montreal Cognitive Assessment (MoCA) score and Immediate Recall Verbatim (IRV) z-score, and higher plasma SLIT2 was associated with a lower MoCA score. In multivariate analysis using single and multiple predictor models, the same significant associations were found when adjusted for age, sex, race, diabetic status, diabetic retinopathy status, glaucoma status, and Apolipoprotein E (APOE) genotype. ConclusionsSLIT2 protein levels are significantly associated with MoCA score and IRV z-score in middle-aged individuals. The relationship remained significant when adjusted for demographics, co-morbidity, and APOE genotype, suggesting SLIT2 may be a sensitive biomarker for detection of mild cognitive impairment and early dementia, and warrants further studies.

neuroscience↗

bioRxiv2025

ZEB2 signaling is essential for ureteral smooth muscle cell differentiation and maintenance

Mowat-Wilson Syndrome (MWS) is a multiple congenital anomaly syndrome caused by mutations in the ZEB2, which plays a critical role in cell fate determination and differentiation during development. Congenital anomalies of the kidney and urinary tract (CAKUT) have been reported in MWS patients. However, the role of ZEB2 in urinary tract development and the cellular and molecular mechanism underlining the CAKUT phenotypes in MWS remains unknown. We performed ZEB2 protein expression analysis in the developing mouse ureter. We generated Zeb2 ureteral mesenchyme-specific conditional knockout mice by crossing Zeb2 floxed mice with Tbx18Cre mice (Zeb2 cKO) and analyzed the urinary tract phenotypes in Zeb2 cKO mice and wild-type littermate controls by gross and histological examination. Ureteral cellular and molecular phenotypes were studied using TAGLN, ACTA2, FOXD1, POSTN, CDH1, TBX18, and SOX9 ureteral cell-specific markers. We found that ZEB2 is expressed in TBX18+ ureteral mesenchymal cells during mouse ureter development. Deletion of Zeb2 in developing ureteral mesenchymal cells causes hydroureter and hydronephrosis phenotypes, leading to obstructive uropathy, kidney failure, and early mortality. Cellular and molecular marker analyses showed that the TAGLN+ACTA2+ ureteral smooth muscle cells (SMCs) layer is not formed in Zeb2 cKO mice at E15.5, but the FOXD1+ and POSTN+ tunica adventitia cells layer is significantly expanded compared to wild-type controls. CDH1+ urothelium cells are reduced considerably in the Zeb2 cKO ureters at E15.5. Mechanistically, we found that Zeb2 cKO mice have significantly decreased TBX18 expression but an increased SOX9 expression in the developing ureter at E14.5 and E15.5 compared to wild-type littermate controls. Our results show that ZEB2 is essential for ureter development by maintaining ureteral mesenchymal cell differentiation into normal ureteral SMCs. Our study also shed new light on the pathological mechanism underlying the developmental abnormalities of the urinary tract phenotypes in MWS patients. Author SummaryHydroureter and hydronephrosis are common congenital anomalies with high incidence (1:100 to 1:500) that can lead to obstructive uropathy and renal failure in the pediatric population. Mowat-Wilson Syndrome (MWS), caused by heterozygous mutations in the ZEB2 gene, is a genetic disease with multiple congenital developmental defects, including hydroureter and hydronephrosis. However, the molecular function of ZEB2 in ureter development and pathogenesis of hydroureter and hydronephrosis remains unknown. Here, we show that ZEB2 is expressed in the developing ureteral mesenchymal cells, and deletion of ZEB2 in ureteral mesenchymal cells leads to ureteral smooth muscle cell loss, which is replaced by tunica adventitia cells causing hydroureter and hydronephrosis phenotype. Hence, our work not only demonstrates the critical role of ZEB2 in ureter development but also provides molecular mechanisms of urinary tract anomalies in MWS patients.

developmental biology↗

bioRxiv2018

Morphogen-Lineage Selector Interactions During Surface Epithelial Commitment

Human embryonic stem cell (hESC) differentiation promises advances in regenerative medicine1-3, yet conversion of hESCs into tissues such as keratinocytes requires a better understanding of epigenetic interactions between the inductive morphogens retinoic acid (RA) and bone morphogenetic protein 4 (BMP), and the master regulator p634,5. Here we develop a robust, defined, keratinocyte differentiation system, and use a multi-dimensional genomics approach to interrogate the contributions of the morphogens and lineage selector to chromatin dynamics during early surface ectoderm commitment. In stark contrast to other master regulators6-9, we find using p63 gain and loss of function hESC lines, that p63 effects major transcriptional changes only after morphogenetic action. Morphogens alter chromatin accessibility and histone modifications, establishing an epigenetic landscape for p63 to modify. In turn, p63 closes chromatin accessibility and promotes the accumulation of repressive H3K27me3 histone modifications at sites distal to where it binds. Surprisingly, cohesin HiChIP10 visualization of genome-wide chromosome conformation reveals that both p63 and the morphogens contribute to dynamic long-range genomic interactions that increase the probability of negative transcriptional regulation at p63 target loci. p63-regulated accessibility, not H3K27me3 deposition, appears to drive early transcriptional changes. We illustrate morphogen-selector interactions by studying p63 negative feedback regulation of TFAP2Ci11, whereby disruption of the single p63 binding site results in a loss of p63-mediated transcriptional control and dramatic increases in TFAP2C and p63 expression. Our study reveals the unexpected dependency of p63 on morphogenetic signaling to control long-range chromatin interactions during tissue specification and provides novel insights into how master regulators specify diverse morphological outcomes.

genetics↗