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Small Molecule GSK-J1 Affects Differentiation of Specific Neuronal Subtypes in Developing Rat Retina

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Abstract

Histone post-translational modification has been shown to play a pivotal role in regulating gene expression and fate determination during the development of the central nervous system. Application of pharmacological blockers that control histone methylation status has been considered a promising avenue to control abnormal developmental processes and diseases as well. In this study, we focused on the role of potent histone demethylase inhibitor GSK-J1 as a blocker of Jumonji domain-containing protein 3 (Jmjd3) in early postnatal retinal development. Jmjd3 participates in different processes such as cell proliferation, apoptosis, differentiation, senescence, and cell reprogramming via demethylation of histone 3 lysine 27 trimethylation status (H3K27 me3). As a first approach, we determined the localization of Jmjd3 in neonate and adult rat retina. We observed that Jmjd3 accumulation is higher in the adult retina, which is consistent with the localization in the differentiated neurons, including ganglion cells in the retina of neonate rats. At this developmental age, we also observed the presence of Jmjd3 in undifferentiated cells. Also, we confirmed that GSK-J1 caused the increase in the H3k27 me3 levels in the retinas of neonate rats. We next examined the functional consequences of GSK-J1 treatment on retinal development. Interestingly, injection of GSK-J1 simultaneously increased the number of proliferative and apoptotic cells. Furthermore, an increased number of immature cells were detected in the outer plexiform layer, with longer neuronal processes. Finally, the influence of GSK-J1 on postnatal retinal cytogenesis was examined. Interestingly, GSK-J1 specifically caused a significant decrease in the number of PKCα-positive cells, which is a reliable marker of rod-on bipolar cells, showing no significant effects on the differentiation of other retinal subtypes. To our knowledge, these data provide the first evidence that in vivo pharmacological blocking of histone demethylase by GSK-J1 affects differentiation of specific neuronal subtypes. In summary, our results indisputably revealed that the application of GSK-J1 could influence cell proliferation, maturation, apoptosis induction, and specific cell determination. With this, we were able to provide evidence that this small molecule can be explored in therapeutic strategies for the abnormal development and diseases of the central nervous system.

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Acknowledgments

We are grateful to Erika Reime Kinjo, Guilherme Shigueto Vilar Higa, and Vera Paschon, Neurogenetics Lab assistants, Animal Facility, at Federal University of ABC.

Funding

This research was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, #2013/07458-2, #2014/16711-6, #2015/04495-0, #2017/26439-0), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, #431000/2016-6, #308608/2014-3), and Universidade Federal do ABC (UFABC).

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Authors and Affiliations

  1. Laboratório de Neurogenética, Centro de Matemática, Computação e Cognição, Universidade Federal do ABC, R. Arcturus 3, Jardim Antares, São Bernardo do Campo, SP, 09606-070, Brazil

    Reza Raeisossadati, Marília Inês Móvio, Lais Takata Walter, Silvia Honda Takada & Alexandre Hiroaki Kihara

  2. Departamento de Biologia Celular e do Desenvolvimento, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil

    Carolina Beltrame Del Debbio

  3. Departamento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil

    Alexandre Hiroaki Kihara

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  1. Reza Raeisossadati
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Correspondence to Alexandre Hiroaki Kihara.

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The experiments on animals were conducted considering the guidelines of the NIH and the Brazilian Society for Laboratory Animals. The experimental protocol (9965240217) was approved by the Ethics Committee of Federal University of ABC.

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Raeisossadati, R., Móvio, M.I., Walter, L.T. et al. Small Molecule GSK-J1 Affects Differentiation of Specific Neuronal Subtypes in Developing Rat Retina. Mol Neurobiol 56, 1972–1983 (2019). https://doi.org/10.1007/s12035-018-1197-3

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