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eNeuro. 2019 Nov 27;6(6). pii: ENEURO.0239-19.2019. doi: 10.1523/ENEURO.0239-19.2019. Print 2019 Nov/Dec.

Loss of Tiparp Results in Aberrant Layering of the Cerebral Cortex.

Author information

1
Institute of Basic Medical Sciences, University of Oslo, Oslo 0372, Norway jason.matthews@medisin.uio.no giulia.grimaldi@medisin.uio.no.
2
Institute of Basic Medical Sciences, University of Oslo, Oslo 0372, Norway.
3
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.

Abstract

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly-ADP-ribose polymerase (TIPARP) is an enzyme that adds a single ADP-ribose moiety to itself or other proteins. Tiparp is highly expressed in the brain; however, its function in this organ is unknown. Here, we used Tiparp-/- mice to determine Tiparp's role in the development of the prefrontal cortex. Loss of Tiparp resulted in an aberrant organization of the mouse cortex, where the upper layers presented increased cell density in the knock-out mice compared with wild type. Tiparp loss predominantly affected the correct distribution and number of GABAergic neurons. Furthermore, neural progenitor cell proliferation was significantly reduced. Neural stem cells (NSCs) derived from Tiparp-/- mice showed a slower rate of migration. Cytoskeletal components, such as α-tubulin are key regulators of neuronal differentiation and cortical development. α-tubulin mono-ADP ribosylation (MAR) levels were reduced in Tiparp-/- cells, suggesting that Tiparp plays a role in the MAR of α-tubulin. Despite the mild phenotype presented by Tiparp-/- mice, our findings reveal an important function for Tiparp and MAR in the correct development of the cortex. Unravelling Tiparp's role in the cortex, could pave the way to a better understanding of a wide spectrum of neurological diseases which are known to have increased expression of TIPARP.

KEYWORDS:

PARP; Tiparp; cortex; cortex layering; mono-ADP ribosylation; post-translational modification

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