Neural Crest Development and Disease

National Institute Of Dental & Craniofacial Research

Investigators

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Abstract

Our recent work has focused on two main aims. First, we completed a multiple-year project of characterizing ectodermal organoids, which faithfully recapitulates human ectoderm patterning of future central nervous system, epidermis and cranial and trunk NC, as well as a diverse selection of NC derivatives —finally offering a comprehensive platform to study neurocristopathies from early induction of pluripotent-like stem cells at the neural plate border to differentiated cells. In this work (Taroc, Perera, Berecz et al, BioRxiv 2025), we used patient-derived iPSCs from DiGeorge Syndrome and healthy relative controls. 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. Second, we finished a chick embryo project where we used fluorescent in situ hybridization to analyze the expression patterns of pluripotency genes PouV (Oct4), Nanog, Klf4 and Lin28A in the growing embryo. Recent work from us has shown that neural crest cells co-express factors known from the core pluripotency complex from the pre-gastrulation stages in the epiblast, which enables their exceptionally high stem cell potential (Pajanoja et al, 2023). However, detailed spatiotemporal data on pluripotency factor expression in vertebrate embryos remain limited, and the distinction between the function of co-expression of pluripotency genes versus their individual expression in the developing embryo is not clear. From head to trunk, we find that while the early ectoderm, including the future epidermis and central nervous system (CNS) domains, in the neural fold stages broadly co-express these genes, their expression profiles differ significantly after neurulation. Nanog expression remains in the hindbrain and vagal migratory NCCs. Klf4 strongly marks the developing floor plate, and Klf4, PouV and Lin28A are expressed also in the neural tube that forms the CNS as well as in the developing somites, implying additional roles for these factors during embryogenesis (Hsin et al., 2025 PMID: 40449070)