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Zfp423, a Joubert syndrome gene, is a domain-specific regulator of cell cycle progression, DNA damage response and Purkinje cell development in the cerebellar primordium

Filippo Casonil, Laura Crocil, Camilla Bosonel, Roberta D’Ambrosio, Aurora Badaloni, Davide Gaudesi, Valeria Barilil, Justyna R. Sarna, Lino Tessarollo, Ottavio Cremona, Richard Hawkes, Søren Warming, G. Giacomo Consalez
doi: https://doi.org/10.1101/139691
Filippo Casonil
1Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
2Università Vita-Salute San Raffaele, Milan, Italy.
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Laura Crocil
1Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
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Camilla Bosonel
1Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
2Università Vita-Salute San Raffaele, Milan, Italy.
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Roberta D’Ambrosio
1Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
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Aurora Badaloni
1Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
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Davide Gaudesi
1Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
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Valeria Barilil
1Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
2Università Vita-Salute San Raffaele, Milan, Italy.
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Justyna R. Sarna
3Department of Clinical Neurosciences and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Alberta, Canada.
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Lino Tessarollo
4Center for Cancer Research, National Cancer Institute, Frederick, MD.
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Ottavio Cremona
1Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
2Università Vita-Salute San Raffaele, Milan, Italy.
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Richard Hawkes
5Department of Cell Biology & Anatomy and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Alberta, Canada.
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Søren Warming
4Center for Cancer Research, National Cancer Institute, Frederick, MD.
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G. Giacomo Consalez
1Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
2Università Vita-Salute San Raffaele, Milan, Italy.
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ABSTRACT

Neurogenesis is a tightly regulated process whose success depends on the ability to balance the expansion/maintenance of an undifferentiated neural progenitor pool with the precisely timed birth of sequential generations of neurons. The Zfp423 gene encodes a 30-Zn-finger transcription factor (TF) that acts as a scaffold in the assembly of complex transcriptional and cellular machineries regulating neural development. While null mutants for Zfp423 feature a severe cerebellar hypoplasia, the underlying mechanism is only partially characterized. Mutations of the human ortholog ZNF423 have been identified in patients carrying cerebellar vermis hypoplasia (CVH) or Joubert Syndrome (JS), associated with other signs of classical ciliopathy outside the central nervous system (CNS). ZNF423 also plays a role in the DNA damage response (DDR). To further characterize the role of ZFP423 in cerebellar neurogenesis, with a focus on Purkinje cells (PC) development, we analyzed two previously undescribed mutant mouse lines carrying allelic in-frame deletions of the corresponding gene, selectively affecting two functionally characterized protein-protein interaction domains, affecting zinc (Zn) fingers 9-20 or 28-30. Some phenotypic defects are allele specific: Zfp423Δ9-20/Δ9-20 mutants exhibit a depletion of the OLIG2+ PC progenitor pool in the cerebellar ventricular zone (VZ). In these mutants, M-phase progenitors display changes in spindle orientation indicative of a precocious switch from symmetric to asymmetric cell division. Conversely, the Zfp423Δ28-30/Δ28-30 primordium displays a sharp decrease in the expression of PC differentiation markers, including CORL2, despite an abundance of cycling PC progenitors. Moreover, and importantly, in both mutants VZ progenitor cell cycle progression is remarkably affected, and factors involved in the DDR are substantially upregulated in the VZ and in postmitotic precursors alike. 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 supports the emerging notion that an impaired DNA damage response may be a key factor in the pathogenesis of JS and other ciliopathies.

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Posted May 18, 2017.
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Zfp423, a Joubert syndrome gene, is a domain-specific regulator of cell cycle progression, DNA damage response and Purkinje cell development in the cerebellar primordium
Filippo Casonil, Laura Crocil, Camilla Bosonel, Roberta D’Ambrosio, Aurora Badaloni, Davide Gaudesi, Valeria Barilil, Justyna R. Sarna, Lino Tessarollo, Ottavio Cremona, Richard Hawkes, Søren Warming, G. Giacomo Consalez
bioRxiv 139691; doi: https://doi.org/10.1101/139691
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Zfp423, a Joubert syndrome gene, is a domain-specific regulator of cell cycle progression, DNA damage response and Purkinje cell development in the cerebellar primordium
Filippo Casonil, Laura Crocil, Camilla Bosonel, Roberta D’Ambrosio, Aurora Badaloni, Davide Gaudesi, Valeria Barilil, Justyna R. Sarna, Lino Tessarollo, Ottavio Cremona, Richard Hawkes, Søren Warming, G. Giacomo Consalez
bioRxiv 139691; doi: https://doi.org/10.1101/139691

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