The development of the mammalian cortex is a complex process that requires the precise coordination of neuronal proliferation, migration, neurite outgrowth and synaptogenesis. Defects in corticogenesis are thought to underlie aspects of several neuropsychiatric disorders including schizophrenia (SCZ). In the past decade, several genes involved in neurodevelopment have been linked to SCZ and related disorders. A number of these genes act in either the canonical WNT or Reelin (RELN) signaling pathways, which have central roles in proliferation and migration, respectively. These pathways are traditionally thought to act independently at different times in the development of a neuron. However, shared molecular factors such as DISC1 exist between these pathways. Our overarching hypothesis is that the WNT and RELN pathways interact to regulate the developmental switch between proliferation and migration. Further, we posit that disruption of genes shared between these pathways, such as DISC1, lead to increased risk for psychiatric disorders. Our lab has established isogenic human induced pluripotent stem cells (iPSCs) that have a targeted mutation at the DISC1 locus near the site of a chr(1;11) balanced translocation linked to major mental disorders. We will use these lines to address if and how this disease-relevant mutation affects certain neurodevelopmental processes. Importantly, phenotypes observed will be examined in hiPSCs derived from human subjects with SCZ harboring the chr(1;11) translocation. Further, in order to examine whether the molecular and cellular phenotypes extend beyond DISC1 disruption, a limited analysis will be performed in hiPSCs from SCZ patients with CNVs linked to mental illness. To complement these in vitro studies, postmortem human brain tissue and rodent models will be utilized in parallel to establish the in vivo relevance of key findings.
In Aim 1, we examine DISC1 isoform expression in isogenic and patient-derived wild-type and mutant lines over neuronal differentiation. We analyze the maturation of these neurons via gene expression profiling, morphometric analyses, and electrophysiological assays.
In Aim 2, we investigate the WNT and RELN signal transduction pathways, and compare the impact of DISC1 disruption with SCZ-linked copy number variants (CNVs) on these pathways. Lastly, in Aim 3 we analyze the effects of DISC1 disruption and SCZ-linked CNVs on proliferation and migration in vivo in the embryonic rodent brain via the complementary methods of in utero electroporation to knock down or overexpress genes and transplantation of human NPCs harboring these disruptions. Taken together, we aim to identify how the effects of these mutations converge to result in altered cortical circuitry and the onset o mental illness. Under this research plan, we take initial steps to compare how specific genetic disruptions with strong effect on risk for mental illness affect developmental signaling pathways and processes in human neuronal cells.

Public Health Relevance

Recent studies have identified mutations that increase risk for schizophrenia and related neuropsychiatric disorders. The goal of this study is to understand how certain mutations lead to mental illness, by using human stem cells to study how brain development is affected by these mutations at the cell and molecular level.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH101148-02
Application #
8841014
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Panchision, David M
Project Start
2014-05-01
Project End
2019-02-28
Budget Start
2015-03-01
Budget End
2016-02-29
Support Year
2
Fiscal Year
2015
Total Cost
$440,551
Indirect Cost
$190,551
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Srikanth, Priya; Lagomarsino, Valentina N; Pearse 2nd, Richard V et al. (2018) Convergence of independent DISC1 mutations on impaired neurite growth via decreased UNC5D expression. Transl Psychiatry 8:245
Srikanth, Priya; Lagomarsino, Valentina N; Muratore, Christina R et al. (2018) Shared effects of DISC1 disruption and elevated WNT signaling in human cerebral organoids. Transl Psychiatry 8:77
Callahan, D G; Taylor, W M; Tilearcio, M et al. (2017) Embryonic mosaic deletion of APP results in displaced Reelin-expressing cells in the cerebral cortex. Dev Biol 424:138-146
Sullivan, Sarah E; Young-Pearse, Tracy L (2017) Induced pluripotent stem cells as a discovery tool for Alzheimer?s disease. Brain Res 1656:98-106
Young-Pearse, Tracy L; Morrow, Eric M (2016) Modeling developmental neuropsychiatric disorders with iPSC technology: challenges and opportunities. Curr Opin Neurobiol 36:66-73
Srikanth, Priya; Han, Karam; Callahan, Dana G et al. (2015) Genomic DISC1 Disruption in hiPSCs Alters Wnt Signaling and Neural Cell Fate. Cell Rep 12:1414-29