Tgfbr1 regulates lateral plate mesoderm and endoderm reorganization during the trunk to tail transition

eLife, Год журнала: 2025, Номер 13

Опубликована: Янв. 28, 2025

During the trunk to tail transition mammalian embryo builds outlets for intestinal and urogenital tracts, lays down primordia hindlimb external genitalia, switches from epiblast/primitive streak (PS) bud as driver of axial extension. Genetic molecular data indicate that Tgfbr1 is a key regulator transition. has been shown control switch neuromesodermal competent cells epiblast chordoneural hinge generate bud. We now show in mouse embryos signaling also controls remodeling lateral plate mesoderm (LPM) embryonic endoderm associated with In absence Tgfbr1, two LPM layers do not converge at end trunk, extending instead separate until caudal extremity, failing activate markers genitalia. The vascular involving dorsal aorta umbilical artery leading connection between extraembryonic circulation was affected mutant embryos. Similar alterations system were observed Isl1 null mutants, indicating this factor acts regulatory cascade downstream LPM-derived tissues. addition, fails expand form endodermal cloaca extend posteriorly gut. present evidence suggesting activity results posterior PS fate after its regression during Our data, together previously reported observations, place top processes controlling

Язык: Английский

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A differential requirement for ciliary transition zone proteins in human and mouse neural progenitor fate specification

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Апрель 5, 2025

Abstract Studying ciliary genes in the context of human central nervous system is crucial for understanding underlying causes neurodevelopmental ciliopathies. Here, we use pluripotent stem cell-derived spinal organoids to reveal distinct functions ciliopathy gene RPGRIP1L humans and mice, uncover an unexplored role cilia axial patterning. Previous research has emphasized Rpgrip1l critical mouse brain cord development through regulation SHH/GLI pathway. show that not required SHH activation or motoneuron lineage commitment progenitors this feature shared by another gene, TMEM67 . Furthermore, -mutant motoneurons adopt hindbrain cervical identities instead caudal brachial identity. Temporal transcriptome analysis reveals antero-posterior patterning defect originates early correlates with loss. These findings provide important insights into neural development.

Язык: Английский

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Dynamic extrinsic pacing of the HOX clock in human axial progenitors controls motor neuron subtype specification

Development, Год журнала: 2021, Номер 148(6)

Опубликована: Март 15, 2021

Rostro-caudal patterning of vertebrates depends on the temporally progressive activation HOX genes within axial stem cells that fuel embryo elongation. Whether pace sequential genes, 'HOX clock', is controlled by intrinsic chromatin-based timing mechanisms or temporal changes in extrinsic cues remains unclear. Here, we studied clock pacing human pluripotent cell-derived progenitors differentiating into diverse spinal cord motor neuron subtypes. We show caudal a dynamic increase FGF signaling. Blocking pathway stalled induction while precocious FGF, alone with GDF11 ligand, accelerated clock. Cells differentiated under generated appropriate posterior subtypes found along embryonic cord. The thus dynamically regulated exposure to secreted cues. Its manipulation factors provides synchronized access multiple neuronal distinct rostro-caudal identities for basic and translational applications.This article has an associated 'The people behind papers' interview.

Язык: Английский

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Isogenic patient-derived organoids reveal early neurodevelopmental defects in spinal muscular atrophy initiation

Cell Reports Medicine, Год журнала: 2024, Номер 5(8), С. 101659 - 101659

Опубликована: Июль 26, 2024

Whether neurodevelopmental defects underlie postnatal neuronal death in neurodegeneration is an intriguing hypothesis only recently explored. Here, we focus on spinal muscular atrophy (SMA), a neuromuscular disorder caused by reduced survival of motor neuron (SMN) protein levels leading to (MN) loss and muscle wasting. Using the first isogenic patient-derived induced pluripotent stem cell (iPSC) model cord organoid (SCO) system, show that SMA SCOs exhibit abnormal morphological development, expression early neural progenitor markers, accelerated MN markers. Longitudinal single-cell RNA sequencing reveals marked specification fewer MNs, favoring mesodermal progenitors cells, bias also seen mouse embryos. Surprisingly, SMN2-to-SMN1 conversion does not fully reverse these developmental abnormalities. These suggest may later degeneration, indicating SMN-increasing interventions might completely amend pathology all patients.

Язык: Английский

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Toward developing human organs via embryo models and chimeras

Cell, Год журнала: 2024, Номер 187(13), С. 3194 - 3219

Опубликована: Июнь 1, 2024

Developing functional organs from stem cells remains a challenging goal in regenerative medicine. Existing methodologies, such as tissue engineering, bioprinting, and organoids, only offer partial solutions. This perspective focuses on two promising approaches emerging for engineering human cells: cell-based embryo models interspecies organogenesis. Both exploit the premise of guiding to mimic natural development. We begin by summarizing what is known about early development blueprint recapitulating organogenesis both chimeras. The latest advances fields are discussed before highlighting technological knowledge gaps be addressed developing could achieved using approaches. conclude discussing challenges facing modeling outlining future prospects advancing toward generation tissues basic research translational applications.

Язык: Английский

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A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Май 3, 2024

Abstract Early childhood tumours arise from transformed embryonic cells, which often carry large copy number alterations (CNA). However, it remains unclear how CNAs contribute to tumourigenesis due a lack of suitable models. Here we employ female human stem cell (hESC) differentiation and single-cell transcriptome epigenome analysis assess the effects chromosome 17q/1q gains, are prevalent in embryonal tumour neuroblastoma (NB). We show that impair specification trunk neural crest (NC) cells their sympathoadrenal derivatives, putative cells-of-origin NB. This effect is exacerbated upon overexpression MYCN , whose amplification co-occurs with Moreover, potentiate pro-tumourigenic mutant NC resemble NB tumours. These changes correlate stepwise aberration developmental transcription factor networks. Together, our results sketch mechanistic framework for CNA-driven initiation

Язык: Английский

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Building consensus in neuromesodermal research: Current advances and future biomedical perspectives

Current Opinion in Cell Biology, Год журнала: 2021, Номер 73, С. 133 - 140

Опубликована: Окт. 28, 2021

Язык: Английский

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Neuromesodermal specification during head-to-tail body axis formation

Current topics in developmental biology/Current Topics in Developmental Biology, Год журнала: 2024, Номер unknown, С. 232 - 271

Опубликована: Янв. 1, 2024

Язык: Английский

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Rostrocaudal patterning and neural crest differentiation of human pre-neural spinal cord progenitors in vitro

Stem Cell Reports, Год журнала: 2022, Номер 17(4), С. 894 - 910

Опубликована: Март 25, 2022

The spinal cord emerges from a niche of neuromesodermal progenitors (NMPs) formed and maintained by WNT/fibroblast growth factor (FGF) signals at the posterior end embryo. NMPs can be generated human pluripotent stem cells hold promise for replacement therapies. However, are transient, which compromises production full range rostrocaudal identities in vitro. Here we report generation NMP-derived pre-neural (PNPs) with cell-like self-renewal capacity. PNPs maintain pre-spinal identity 7–10 passages, dividing to self-renew make neural crest progenitors, while gradually adopting more activating colinear HOX gene expression. clock halted through GDF11-mediated signal inhibition produce PNP NC population thoracic that up 30 passages.

Язык: Английский

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Tgfbr1 controls developmental plasticity between the hindlimb and external genitalia by remodeling their regulatory landscape

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Март 20, 2024

Abstract The hindlimb and external genitalia of present-day tetrapods are thought to derive from an ancestral common primordium that evolved generate a wide diversity structures adapted for efficient locomotion mating in the ecological niche occupied by species. We show despite long evolutionary distance condition, early mouse preserved capacity take fates. In absence Tgfbr1 , pericloacal mesoderm generates extra pair hindlimbs at expense genitalia. It has been shown genital primordia share many their key regulatory factors. controls response those factors modulating accessibility status elements control gene networks leading formation or structures. Our work uncovers remarkable tissue plasticity with potential implications evolution hindlimb/genital area tetrapods, identifies additional mechanism activity might also contribute other physiological pathological processes.

Язык: Английский

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