Zfp423/ZNF423 regulates cell cycle progression, the mode of cell division and the DNA-damage response in purkinje neuron progenitors

F Casoni, L Croci, C Bosone, R D’Ambrosio, A Badaloni, D Gaudesi, V Barili, JR Sarna, L Tessarollo, O Cremona, R Hawkes, S Warming, GG Consalez

Research output: Contribution to journalArticle

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Abstract

The Zfp423/ZNF423 gene encodes a 30-zinc-finger transcription factor involved in key developmental pathways. Although null Zfp423 mutants develop cerebellar malformations, the underlying mechanism remains unknown. ZNF423 mutations are associated with Joubert Syndrome, a ciliopathy causing cerebellar vermis hypoplasia and ataxia. ZNF423 participates in the DNA-damage response (DDR), raising questions regarding its role as a regulator of neural progenitor cell cycle progression in cerebellar development. To characterize in vivo the function of ZFP423 in neurogenesis, we analyzed allelic murine mutants in which distinct functional domains are deleted. One deletion impairs mitotic spindle orientation, leading to premature cell cycle exit and Purkinje cell (PC) progenitor pool deletion. The other deletion impairs PC differentiation. In both mutants, cell cycle progression is remarkably delayed and DDR markers are upregulated in cerebellar ventricular zone progenitors. Our in vivo evidence sheds light on the domain-specific roles played by ZFP423 in different aspects of PC progenitor development, and at the same time strengthens the emerging notion that an impaired DDR may be a key factor in the pathogenesis of JS and other ciliopathies. © 2017. Published by The Company of Biologists Ltd.
Original languageEnglish
Pages (from-to)3686-3697
Number of pages12
JournalDevelopment (Cambridge)
Volume144
Issue number20
DOIs
Publication statusPublished - 2017

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Purkinje Cells
Cell Division
DNA Damage
Cell Cycle
Cerebellar Ataxia
Spindle Apparatus
Zinc Fingers
Neurogenesis
Cell Differentiation
Transcription Factors
Stem Cells
Mutation
Genes
Ciliopathies

Cite this

Zfp423/ZNF423 regulates cell cycle progression, the mode of cell division and the DNA-damage response in purkinje neuron progenitors. / Casoni, F; Croci, L; Bosone, C; D’Ambrosio, R; Badaloni, A; Gaudesi, D; Barili, V; Sarna, JR; Tessarollo, L; Cremona, O; Hawkes, R; Warming, S; Consalez, GG.

In: Development (Cambridge), Vol. 144, No. 20, 2017, p. 3686-3697.

Research output: Contribution to journalArticle

Casoni, F ; Croci, L ; Bosone, C ; D’Ambrosio, R ; Badaloni, A ; Gaudesi, D ; Barili, V ; Sarna, JR ; Tessarollo, L ; Cremona, O ; Hawkes, R ; Warming, S ; Consalez, GG. / Zfp423/ZNF423 regulates cell cycle progression, the mode of cell division and the DNA-damage response in purkinje neuron progenitors. In: Development (Cambridge). 2017 ; Vol. 144, No. 20. pp. 3686-3697.
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abstract = "The Zfp423/ZNF423 gene encodes a 30-zinc-finger transcription factor involved in key developmental pathways. Although null Zfp423 mutants develop cerebellar malformations, the underlying mechanism remains unknown. ZNF423 mutations are associated with Joubert Syndrome, a ciliopathy causing cerebellar vermis hypoplasia and ataxia. ZNF423 participates in the DNA-damage response (DDR), raising questions regarding its role as a regulator of neural progenitor cell cycle progression in cerebellar development. To characterize in vivo the function of ZFP423 in neurogenesis, we analyzed allelic murine mutants in which distinct functional domains are deleted. One deletion impairs mitotic spindle orientation, leading to premature cell cycle exit and Purkinje cell (PC) progenitor pool deletion. The other deletion impairs PC differentiation. In both mutants, cell cycle progression is remarkably delayed and DDR markers are upregulated in cerebellar ventricular zone progenitors. Our in vivo evidence sheds light on the domain-specific roles played by ZFP423 in different aspects of PC progenitor development, and at the same time strengthens the emerging notion that an impaired DDR may be a key factor in the pathogenesis of JS and other ciliopathies. {\circledC} 2017. Published by The Company of Biologists Ltd.",
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AU - Croci, L

AU - Bosone, C

AU - D’Ambrosio, R

AU - Badaloni, A

AU - Gaudesi, D

AU - Barili, V

AU - Sarna, JR

AU - Tessarollo, L

AU - Cremona, O

AU - Hawkes, R

AU - Warming, S

AU - Consalez, GG

PY - 2017

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N2 - The Zfp423/ZNF423 gene encodes a 30-zinc-finger transcription factor involved in key developmental pathways. Although null Zfp423 mutants develop cerebellar malformations, the underlying mechanism remains unknown. ZNF423 mutations are associated with Joubert Syndrome, a ciliopathy causing cerebellar vermis hypoplasia and ataxia. ZNF423 participates in the DNA-damage response (DDR), raising questions regarding its role as a regulator of neural progenitor cell cycle progression in cerebellar development. To characterize in vivo the function of ZFP423 in neurogenesis, we analyzed allelic murine mutants in which distinct functional domains are deleted. One deletion impairs mitotic spindle orientation, leading to premature cell cycle exit and Purkinje cell (PC) progenitor pool deletion. The other deletion impairs PC differentiation. In both mutants, cell cycle progression is remarkably delayed and DDR markers are upregulated in cerebellar ventricular zone progenitors. Our in vivo evidence sheds light on the domain-specific roles played by ZFP423 in different aspects of PC progenitor development, and at the same time strengthens the emerging notion that an impaired DDR may be a key factor in the pathogenesis of JS and other ciliopathies. © 2017. Published by The Company of Biologists Ltd.

AB - The Zfp423/ZNF423 gene encodes a 30-zinc-finger transcription factor involved in key developmental pathways. Although null Zfp423 mutants develop cerebellar malformations, the underlying mechanism remains unknown. ZNF423 mutations are associated with Joubert Syndrome, a ciliopathy causing cerebellar vermis hypoplasia and ataxia. ZNF423 participates in the DNA-damage response (DDR), raising questions regarding its role as a regulator of neural progenitor cell cycle progression in cerebellar development. To characterize in vivo the function of ZFP423 in neurogenesis, we analyzed allelic murine mutants in which distinct functional domains are deleted. One deletion impairs mitotic spindle orientation, leading to premature cell cycle exit and Purkinje cell (PC) progenitor pool deletion. The other deletion impairs PC differentiation. In both mutants, cell cycle progression is remarkably delayed and DDR markers are upregulated in cerebellar ventricular zone progenitors. Our in vivo evidence sheds light on the domain-specific roles played by ZFP423 in different aspects of PC progenitor development, and at the same time strengthens the emerging notion that an impaired DDR may be a key factor in the pathogenesis of JS and other ciliopathies. © 2017. Published by The Company of Biologists Ltd.

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