Biology subjects

Kerosuo, L.

Publications and source records attributed to Kerosuo, L..

5 recordsLinked to original sources

bioRxiv2026

Studies of mice with a large deletion of the ARPKD-associated Pkhd1 locus likely explain its GWAS association with glaucoma in humans

PKHD1, the gene primarily mutated in human autosomal recessive polycystic kidney disease, is one of the top 20 genes associated with primary open angle glaucoma (POAG) and associated endophenotypes in Genome-Wide Association Studies. Here, we show that Pkhd1del3-67/del3-67 mutant mice develop congenital glaucoma due to anterior segment dysgenesis. Using a combination of genetic, epigenetic, bioinformatics and mouse developmental biology approaches, we show that Pkhd1del3-67/del3-67 mice lack Tfap2b and AP-2{beta} expression in a subset of periocular mesenchymal cells at E13.5 and its derivatives. Our data suggest that the Pkhd1del3-67 deletion disrupts features of the Pkhd1-Tfap2b genomic architecture essential for Tfap2b cell-specific activities. Consistent with this model, Pkhd1del3-67/+;Tfap2bko/+trans-heterozygotes lack Tfap2b and AP-2{beta} in relevant cell-types and have similar eye abnormalities as neural crest cell-specific Tfap2bko mutants. These findings provide a likely causal explanation for how SNPs associated with PKHD1 are functionally linked to POAG and add insight into understanding the complexity of disease-causing SNP associations and gene regulatory mechanisms.

genetics↗

bioRxiv2025

Integrated Single-cell Analysis Uncovers Regulatory Logic of Cranial Ectoderm Development

Embryonic ectoderm patterning in the cranial region establishes the neural plate, neural crest, sensory placodes, and non-neural ectoderm in coordination with the underlying mesoderm and endoderm. Although many studies have defined the signaling pathways and transcriptional regulators driving individual lineage specification, the temporal and spatial coordination among adjacent tissues remains poorly understood. To address this, we analyzed a single-cell RNA sequencing (scRNAseq) data set of a developmental series from the chick midbrain axial level, spanning stages from gastrulation to post-neurulation. Focusing on a defined region enabled high-resolution analysis of transcriptional dynamics and subpopulation transitions. Transcription factor downstream activity inference identified several ubiquitously expressed chromatin and histone modifiers--previously not associated with ectodermal patterning--that exhibit canonical downstream activity spatiotemporally restricted to specific developing domains. Moreover, we uncovered genes that remain canonical downstream activity throughout the progression of individual ectodermal domains, while others displayed negative activity scores, reflecting a repressed or alternatively a non-canonical downstream activity status that changed between cell types and developmental stage but was independent of transcription factor binding availability status on open chromatin. Finally, ligand-receptor interaction analyses across germ layers highlighted global signaling networks coordinating early embryogenesis, which were verified by in situ hybridization-based gene expression data. In sum, our study provides novel insights into the gene regulatory inputs that shape ectodermal cell fate decisions during neurulation and establishes a new framework for analyzing scRNAseq data to understand tissue patterning over developmental time.

developmental biology↗

bioRxiv2025

Human ectodermal organoids reveal the cellular origin of DiGeorge Syndrome

Neurocristopathies account for half of all birth defects and several cancers highlighting the need to understand early neural crest (NC) development, for which suitable human models dont exist. Here, we present a pluripotent-stem-cell-based 3D ectodermal organoid model that faithfully recapitulates early ectodermal patterning of future central nervous system, epidermis and cranial and trunk NC, as well as a diverse selection of NC derivatives --offering a comprehensive platform to study neurocristopathies from early induction of pluripotent-like stem cells at the neural plate border to differentiated cells. DiGeorge syndrome (DGS) is caused by a hemizygous microdeletion of [~]fifty genes, many of which play broad roles during embryogenesis. While DGS is traditionally considered to originate from all germ layers, its clinical manifestations--including craniofacial anomalies, cardiac outflow tract defects, thymic hypoplasia and thyroid dysfunction--are consistent with tissues requiring NC contributions. This raises the question why DGS mainly manifest in organs of NC origin? Using patient-derived iPSCs, we show that DGS organoids display reduced pluripotency gene expression and impaired maintenance of ectodermal stem cells, leading to defective NC specification, posteriorization of cranial NC, and failure to form cartilage. We identify a small subset of genes within the DGS deletion as potential drivers of these early NC defects. Consequently, impaired NC cells are further affected during cranial and vagal mesenchyme maturation, likely worsened by hemizygosity of additional DGS genes that individually, without the initial NC defect, are insufficient to cause the disease. We hypothesize that DGS is primarily, or possibly entirely, a neurocristopathy.

developmental biology↗

bioRxiv2022

A tissue-specific ubiquitin switch coordinates brain, craniofacial, and skin development

The molecular mechanisms that coordinate patterning of the embryonic ectoderm into spatially distinct lineages to form the nervous system, epidermis, and craniofacial structures are unclear. Here, biochemical disease-variant profiling reveals a posttranslational pathway that drives early ectodermal differentiation in the vertebrate head. The anteriorly expressed ubiquitin ligase CRL3-KLHL4 restricts signaling of the ubiquitous cytoskeletal regulator CDC42. The major substrate of CRL3-KLHL4 is the canonical CDC42 effector kinase PAK1 that monoubiquitylation switches into a CDC42 inhibitor. Loss of CRL3-KLHL4 or a disease-associated KLHL4 variant reduce PAK1 ubiquitylation causing overactivation of CDC42 signaling and defective ectodermal patterning and neurulation. Thus, tissue-specific, ubiquitin-dependent restriction of CDC42 signaling is essential for face, brain, and skin formation, demonstrating how cell-fate and morphometric changes are coordinated for faithful organ development.

developmental biology↗

bioRxiv2018

Maintaining trunk neural crest cells as crestospheres

Neural crest cells have broad migratory and differentiative ability that differs according to their axial level of origin. However, their transient nature has limited understanding of their stem cell and self-renewal properties. While an in vitro culture method has made it possible to maintain cranial neural crest cells as self-renewing multipotent crestospheres (Kerosuo et al., 2015), these same conditions failed to preserve trunk neural crest in a stem-like state. Here we optimize culture conditions for maintenance of trunk crestospheres, comprised of both neural crest stem and progenitor cells. Trunk crestospheres display elevated expression of neural crest cell markers as compared to those characteristic of neural tube or mesodermal fates. Moreover, trunk crestospheres have increased expression of trunk-related markers as compared to cranial genes. Finally, we use lentiviral transduction as a tool to manipulate gene expression in trunk crestospheres. Taken together, this method enables long-term in vitro maintenance and manipulation of trunk neural crest cells in a premigratory stem or early progenitor state to probe the mechanisms underlying their stemness and lineage decisions.\n\nHighlightsO_LITrunk-derived multipotent neural crest stem cells can be cultured as crestospheres\nC_LIO_LITrunk-derived crestospheres require different conditions than cranial\nC_LIO_LITrunk crestospheres consist of neural crest stem and progenitor cells\nC_LIO_LITrunk crestospheres can be efficiently transduced using lentiviral vectors\nC_LI

developmental biology↗