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

Author(s)

Raeisossadati, Reza ^[1] ; Movio, Marilia Ines ^[1] ; Walter, Lais Takata ^[1] ; Takada, Silvia Honda ^[1] ; Del Debbio, Carolina Beltrame ^[2] ; Kihara, Alexandre Hiroaki ^{[1, 3]}

Affiliation

^[1] Univ Fed ABC, Lab Neurogenet, Ctr Matemat Comp & Cognicao, R Arcturus 3, BR-09606070 Sao Bernardo Do Campo, SP - Brazil

^[2] Univ Sao Paulo, Dept Biol Celular & Desenvolvimento, Inst Ciencias Biomed, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Dept Fisiol & Biofis, Inst Ciencias Biomed, Sao Paulo - Brazil

• Document type: Journal article
• Source: Molecular Neurobiology; v. 56, n. 3, p. 1972-1983, MAR 2019.
• Web of Science Citations: 2

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 PKC-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. (AU)

• FAPESP's process: 17/26439-0 - An interdisciplnary approach on the role of gap junctions and miRNAs in the development and degeneration of the nervous system
• Grantee: Alexandre Hiroaki Kihara
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/07458-2 - Epigenetic-related control of neural differentiation in retinal development
• Grantee: Seyed Reza Raeisossadati
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 14/16711-6 - MicroRNAs and cell coupling interplay in the development, adaptation and degeneration of the nervous system
• Grantee: Alexandre Hiroaki Kihara
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/04495-0 - Nitric oxide effect in the modulation of the chemical and electric synapses during retinal development
• Grantee: Lais Takata Walter
• Support Opportunities: Scholarships in Brazil - Doctorate