PT  - JOURNAL ARTICLE
AU  - Giulia Grimaldi
AU  - Barbora Vagaska
AU  - Oleksandr Ievglevskyi
AU  - Elena Kondratskaya
AU  - Joel Glover
AU  - Jason Matthews
TI  - Loss of Tiparp results in aberrant layering of the cerebral cortex
AID  - 10.1523/ENEURO.0239-19.2019
DP  - 2019 Nov 08
TA  - eneuro
PG  - ENEURO.0239-19.2019
4099  - http://www.eneuro.org/content/early/2019/11/08/ENEURO.0239-19.2019.short
4100  - http://www.eneuro.org/content/early/2019/11/08/ENEURO.0239-19.2019.full
AB  - 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 knockout mice compared with wildtype. Tiparp loss predominantly affected the correct distribution and number of GABAergic neurons. Furthermore, neural progenitor cell proliferation was significantly reduced. Neural stem cells 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 levels were reduced in Tiparp-/- cells, suggesting the Tiparp plays a role in the mono-ADP-ribosylation of α-tubulin. Despite the mild phenotype presented by Tiparp-/- mice, our findings reveal an important function for Tiparp and mono-ADP-ribosylation 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 the TIPARP gene.Significance Statement TCDD-inducible poly-ADP-ribose polymerase (TIPARP) is an enzyme which adds a single ADP-ribose moiety to itself or other proteins and is highly expressed in the brain. However, its function in this organ remains unknown. Here we show that Tiparp affects neural progenitor cell proliferation and migration, and its loss leads to aberrant organization of the mouse cortex, predominantly by disrupting the correct distribution and number of GABAergic neurons. Cytoskeletal components, such as α-tubulin, are key regulators of neuronal differentiation and cortical development, here we show that Tiparp is part of a complex that interacts with α-tubulin and plays a role in its mono-ADP-ribosylation. Despite the mild phenotype presented by the Tiparp knockout mouse our findings reveal an important function of mono-ADP-ribosylation by this enzyme in the correct development of the cortex.