Increased p53 signaling impairs neural differentiation in HUWE1-promoted intellectual disabilities

Rossana Aprigliano; Merdane Ezgi Aksu; Stefano Bradamante; Boris Mihaljevic; Wei Wang; Kristin Rian; Nicola P Montaldo; Kayla Mae Grooms; Sarah L Fordyce Martin; Diana L Bordin; Matthias Bosshard; Yunhui Peng; Emil Alexov; Cindy Skinner; Nina-Beate Liabakk; Gareth J Sullivan; Magnar Bjørås; Charles E Schwartz; Barbara van Loon

doi:10.1016/j.xcrm.2021.100240

Increased p53 signaling impairs neural differentiation in HUWE1-promoted intellectual disabilities

Rossana Aprigliano, Merdane Ezgi Aksu, Stefano Bradamante, Boris Mihaljevic, Wei Wang, Kristin Rian, Nicola P Montaldo, Kayla Mae Grooms, Sarah L Fordyce Martin, Diana L Bordin, Matthias Bosshard, Yunhui Peng, Emil Alexov, Cindy Skinner, Nina-Beate Liabakk, Gareth J Sullivan, Magnar Bjørås, Charles E Schwartz, Barbara van Loon^*

^*Corresponding author for this work

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

Essential E3 ubiquitin ligase HUWE1 (HECT, UBA, and WWE domain containing 1) regulates key factors, such as p53. Although mutations in HUWE1 cause heterogenous neurodevelopmental X-linked intellectual disabilities (XLIDs), the disease mechanisms common to these syndromes remain unknown. In this work, we identify p53 signaling as the central process altered in HUWE1-promoted XLID syndromes. By focusing on Juberg-Marsidi syndrome (JMS), one of the severest XLIDs, we show that increased p53 signaling results from p53 accumulation caused by HUWE1 p.G4310R destabilization. This further alters cell-cycle progression and proliferation in JMS cells. Modeling of JMS neurodevelopment reveals majorly impaired neural differentiation accompanied by increased p53 signaling. The neural differentiation defects can be successfully rescued by reducing p53 levels and restoring the expression of p53 target genes, in particular CDKN1A/p21. In summary, our findings suggest that increased p53 signaling underlies HUWE1-promoted syndromes and impairs XLID JMS neural differentiation.

Original language	English
Article number	100240
Number of pages	18
Journal	Cell reports. Medicine
Volume	2
Issue number	4
Early online date	8 Apr 2021
DOIs	https://doi.org/10.1016/j.xcrm.2021.100240
Publication status	Published - 20 Apr 2021

Keywords

X-linked intellectual disability
E3 ubiquitin ligase
HUWE1
p53
Neurodevelopment

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© 2021 The Author(s). This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0/).
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Aprigliano, R., Aksu, M. E., Bradamante, S., Mihaljevic, B., Wang, W., Rian, K., Montaldo, N. P., Grooms, K. M., Fordyce Martin, S. L., Bordin, D. L., Bosshard, M., Peng, Y., Alexov, E., Skinner, C., Liabakk, N.-B., Sullivan, G. J., Bjørås, M., Schwartz, C. E., & van Loon, B. (2021). Increased p53 signaling impairs neural differentiation in HUWE1-promoted intellectual disabilities. Cell reports. Medicine, 2(4), Article 100240. https://doi.org/10.1016/j.xcrm.2021.100240

@article{678071f3363a44fbab71e6caad0a55bc,

title = "Increased p53 signaling impairs neural differentiation in HUWE1-promoted intellectual disabilities",

abstract = "Essential E3 ubiquitin ligase HUWE1 (HECT, UBA, and WWE domain containing 1) regulates key factors, such as p53. Although mutations in HUWE1 cause heterogenous neurodevelopmental X-linked intellectual disabilities (XLIDs), the disease mechanisms common to these syndromes remain unknown. In this work, we identify p53 signaling as the central process altered in HUWE1-promoted XLID syndromes. By focusing on Juberg-Marsidi syndrome (JMS), one of the severest XLIDs, we show that increased p53 signaling results from p53 accumulation caused by HUWE1 p.G4310R destabilization. This further alters cell-cycle progression and proliferation in JMS cells. Modeling of JMS neurodevelopment reveals majorly impaired neural differentiation accompanied by increased p53 signaling. The neural differentiation defects can be successfully rescued by reducing p53 levels and restoring the expression of p53 target genes, in particular CDKN1A/p21. In summary, our findings suggest that increased p53 signaling underlies HUWE1-promoted syndromes and impairs XLID JMS neural differentiation.",

keywords = "X-linked intellectual disability, E3 ubiquitin ligase, HUWE1, p53, Neurodevelopment",

author = "Rossana Aprigliano and Aksu, {Merdane Ezgi} and Stefano Bradamante and Boris Mihaljevic and Wei Wang and Kristin Rian and Montaldo, {Nicola P} and Grooms, {Kayla Mae} and {Fordyce Martin}, {Sarah L} and Bordin, {Diana L} and Matthias Bosshard and Yunhui Peng and Emil Alexov and Cindy Skinner and Nina-Beate Liabakk and Sullivan, {Gareth J} and Magnar Bj{\o}r{\aa}s and Schwartz, {Charles E} and {van Loon}, Barbara",

note = "Funding: This work was supported by the Central Norway Regional Health Authority (90270800 to B.v.L.) and the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology (46055600-91 to B.v.L.). It was supported in part by an Onsager Fellowship (to B.v.L.), a NINDS grant (1R01NS07385A to C.E.S.), and a grant from the South Carolina Department of Disabilities and Special Needs (SCDDSN). The RNA library preparation and sequencing were performed at the Genomics Core Facility (GCF), and microscopy was performed at the Cellular and Molecular Imaging Core Facility (CMIC), Norwegian University of Science and Technology (NTNU). GCF and CMIC are funded by the Faculty of Medicine and Health Sciences at NTNU and Central Norway Regional Health Authority.",

year = "2021",

month = apr,

day = "20",

doi = "10.1016/j.xcrm.2021.100240",

language = "English",

volume = "2",

journal = "Cell reports. Medicine",

issn = "2666-3791",

publisher = "Cell Press",

number = "4",

}

Aprigliano, R, Aksu, ME, Bradamante, S, Mihaljevic, B, Wang, W, Rian, K, Montaldo, NP, Grooms, KM, Fordyce Martin, SL, Bordin, DL, Bosshard, M, Peng, Y, Alexov, E, Skinner, C, Liabakk, N-B, Sullivan, GJ, Bjørås, M, Schwartz, CE & van Loon, B 2021, 'Increased p53 signaling impairs neural differentiation in HUWE1-promoted intellectual disabilities', Cell reports. Medicine, vol. 2, no. 4, 100240. https://doi.org/10.1016/j.xcrm.2021.100240

TY - JOUR

T1 - Increased p53 signaling impairs neural differentiation in HUWE1-promoted intellectual disabilities

AU - Aprigliano, Rossana

AU - Aksu, Merdane Ezgi

AU - Bradamante, Stefano

AU - Mihaljevic, Boris

AU - Wang, Wei

AU - Rian, Kristin

AU - Montaldo, Nicola P

AU - Grooms, Kayla Mae

AU - Fordyce Martin, Sarah L

AU - Bordin, Diana L

AU - Bosshard, Matthias

AU - Peng, Yunhui

AU - Alexov, Emil

AU - Skinner, Cindy

AU - Liabakk, Nina-Beate

AU - Sullivan, Gareth J

AU - Bjørås, Magnar

AU - Schwartz, Charles E

AU - van Loon, Barbara

N1 - Funding: This work was supported by the Central Norway Regional Health Authority (90270800 to B.v.L.) and the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology (46055600-91 to B.v.L.). It was supported in part by an Onsager Fellowship (to B.v.L.), a NINDS grant (1R01NS07385A to C.E.S.), and a grant from the South Carolina Department of Disabilities and Special Needs (SCDDSN). The RNA library preparation and sequencing were performed at the Genomics Core Facility (GCF), and microscopy was performed at the Cellular and Molecular Imaging Core Facility (CMIC), Norwegian University of Science and Technology (NTNU). GCF and CMIC are funded by the Faculty of Medicine and Health Sciences at NTNU and Central Norway Regional Health Authority.

PY - 2021/4/20

Y1 - 2021/4/20

N2 - Essential E3 ubiquitin ligase HUWE1 (HECT, UBA, and WWE domain containing 1) regulates key factors, such as p53. Although mutations in HUWE1 cause heterogenous neurodevelopmental X-linked intellectual disabilities (XLIDs), the disease mechanisms common to these syndromes remain unknown. In this work, we identify p53 signaling as the central process altered in HUWE1-promoted XLID syndromes. By focusing on Juberg-Marsidi syndrome (JMS), one of the severest XLIDs, we show that increased p53 signaling results from p53 accumulation caused by HUWE1 p.G4310R destabilization. This further alters cell-cycle progression and proliferation in JMS cells. Modeling of JMS neurodevelopment reveals majorly impaired neural differentiation accompanied by increased p53 signaling. The neural differentiation defects can be successfully rescued by reducing p53 levels and restoring the expression of p53 target genes, in particular CDKN1A/p21. In summary, our findings suggest that increased p53 signaling underlies HUWE1-promoted syndromes and impairs XLID JMS neural differentiation.

AB - Essential E3 ubiquitin ligase HUWE1 (HECT, UBA, and WWE domain containing 1) regulates key factors, such as p53. Although mutations in HUWE1 cause heterogenous neurodevelopmental X-linked intellectual disabilities (XLIDs), the disease mechanisms common to these syndromes remain unknown. In this work, we identify p53 signaling as the central process altered in HUWE1-promoted XLID syndromes. By focusing on Juberg-Marsidi syndrome (JMS), one of the severest XLIDs, we show that increased p53 signaling results from p53 accumulation caused by HUWE1 p.G4310R destabilization. This further alters cell-cycle progression and proliferation in JMS cells. Modeling of JMS neurodevelopment reveals majorly impaired neural differentiation accompanied by increased p53 signaling. The neural differentiation defects can be successfully rescued by reducing p53 levels and restoring the expression of p53 target genes, in particular CDKN1A/p21. In summary, our findings suggest that increased p53 signaling underlies HUWE1-promoted syndromes and impairs XLID JMS neural differentiation.

KW - X-linked intellectual disability

KW - E3 ubiquitin ligase

KW - HUWE1

KW - p53

KW - Neurodevelopment

U2 - 10.1016/j.xcrm.2021.100240

DO - 10.1016/j.xcrm.2021.100240

M3 - Article

C2 - 33948573

SN - 2666-3791

VL - 2

JO - Cell reports. Medicine

JF - Cell reports. Medicine

IS - 4

M1 - 100240

ER -

Increased p53 signaling impairs neural differentiation in HUWE1-promoted intellectual disabilities

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