Author response: Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons

An, Disi; Fujiki, Ryosuke; Iannitelli, Dylan E.; Smerdon, John W.; Maity, Shuvadeep; Rose, Matthew F.; Gelber, Alon; Wanaselja, Elizabeth K; Yagudayeva, Ilona; Lee, Joun Y.; Vogel, Christine; Wichterle, Hynek; Engle, Elizabeth C.; Mazzoni, Esteban O.

doi:10.7554/elife.44423.026

Cited by 3 publications

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“…The A-P axial identity of PSC derivatives is likely to shape their functionality and developmental/regenerative potential, as demonstrated by xenotransplantation experiments in animal models (Kadoya et al, 2016;Peljto et al, 2010). As various congenital birth defects and neurodegenerative conditions affect certain cell types in an axial level-specific manner (Box 2), their in vitro modelling relies not only on generating from PSCs cell populations of the correct lineage, but also the appropriate axial identity (Allodi et al, 2019;An et al, 2019;Gordon et al, 2014;Vega-Lopez et al, 2018).…”

Section: Axial Progenitors In Vitromentioning

confidence: 99%

Understanding axial progenitor biology in vivo and in vitro

2021

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The generation of the components that make up the embryonic body axis, such as the spinal cord and vertebral column, takes place in an anterior-to-posterior (head-to-tail) direction. This process is driven by the coordinated production of various cell types from a pool of posteriorly-located axial progenitors. Here, we review the key features of this process and the biology of axial progenitors, including neuromesodermal progenitors, the common precursors of the spinal cord and trunk musculature. We discuss recent developments in the in vitro production of axial progenitors and their potential implications in disease modelling and regenerative medicine.

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Section: Axial Progenitors In Vitromentioning

confidence: 99%

Understanding axial progenitor biology in vivo and in vitro

2021

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Dynamic extrinsic pacing of theHOXclock in human axial progenitors controls motor neuron subtype specification

Mouilleau

Vaslin

Gribaudo

et al. 2020

Preprint

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Rostro-caudal patterning of vertebrates depends on the temporally progressive activation of HOX 1 genes within axial stem cells that fuel axial embryo elongation. Whether HOX genes sequential 2 activation, the "HOX clock", is paced by intrinsic chromatin-based timing mechanisms or by 3 temporal changes in extrinsic cues remains unclear. Here, we studied HOX clock pacing in 4 human pluripotent stem cells differentiating into spinal cord motor neuron subtypes which are 5 progenies of axial progenitors. We show that the progressive activation of caudal HOX genes in 6 axial progenitors is controlled by a dynamic increase in FGF signaling. Blocking FGF pathway 7 stalled induction of HOX genes, while precocious increase in FGF alone, or with GDF11 ligand, 8 accelerated the HOX clock. Cells differentiated under accelerated HOX induction generated 9 appropriate posterior motor neuron subtypes found along the human embryonic spinal cord. The 10 HOX clock is thus dynamically paced by exposure parameters to secreted cues. Its manipulation 11 by extrinsic factors alleviates temporal requirements to provide unprecedented synchronized 12 access to human cells of multiple, defined, rostro-caudal identities for basic and translational 13 applications. , et al. (2013). Accelerated highyield generation of limb-innervating motor neurons from human stem cells. J. Neurosci. 33, 574-586. ., et al. (2019). Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons. Elife 8,.

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

et al. 2021

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

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Author response: Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons

Cited by 3 publications

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Understanding axial progenitor biology in vivo and in vitro

Understanding axial progenitor biology in vivo and in vitro

Dynamic extrinsic pacing of theHOXclock in human axial progenitors controls motor neuron subtype specification

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

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