Sex-dimorphic effects of biogenesis of lysosome-related organelles complex-1 deficiency on mouse perinatal brain development

• Type of Material: Article
• Authors: Frank Y Lee, University of California Los Angeles; Jennifer Larimore, Emory University; Victor Faundez, Emory University; Esteban C Dell'Angelica, University of California Los Angeles; Cristina A Ghiani, University of California Los Angeles
• Language: English
• Date: 2020-05-20
• Publisher: WILEY
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020 Wiley Periodicals, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1002/jnr.24620
• Title of Journal or Parent Work: JOURNAL OF NEUROSCIENCE RESEARCH
• Volume: 99
• Issue: 1
• Start Page: 67
• End Page: 89
• Grant/Funding Information: Funding was provided by National Institutes of Health grants R01GM112942 and R01GM112942S1 to ECD & CAG; 1R56MH111459 and 1RF1AG060285 to VF.; Core equipment used in this study was supported by the Eunice Kennedy Shriver National Institute of Child Health Development under award number: 5U54HD087101.
• Keywords: IDENTIFICATION; CA1 pyramidal cell layer; AB_476744; AB_2811303; AB_2285132; AB_396354; sex differences; PALLIDIN; pallidin; AB_2564645; PROTEIN; SANDY; BLOC-1; AB_90959; AB_91800; Science & Technology; MUTATION; MOLECULAR-MECHANISMS; process outgrowth; radial glia; DYSBINDIN-1 MUTANT; RRID; Life Sciences & Biomedicine; AB_561007; dysbindin; Neurosciences; Neurosciences & Neurology; GENE DTNBP1; REELIN; hippocampus

Abstract

The function(s) of the Biogenesis of Lysosome-related Organelles Complex-1 (BLOC-1) during brain development is to date largely unknown. Here, we investigated how its absence alters the trajectory of postnatal brain development using as model the pallid mouse. Most of the defects observed early postnatally in the mutant mice were more prominent in males than in females and in the hippocampus. Male mutant mice, but not females, had smaller brains as compared to sex-matching wild types at postnatal day 1 (P1), this deficit was largely recovered by P14 and P45. An abnormal cytoarchitecture of the pyramidal cell layer of the hippocampus was observed in P1 pallid male, but not female, or juvenile mice (P45), along with severely decreased expression levels of the radial glial marker Glutamate-Aspartate Transporter. Transcriptomic analyses showed that the overall response to the lack of functional BLOC-1 was more pronounced in hippocampi at P1 than at P45 or in the cerebral cortex. These observations suggest that absence of BLOC-1 renders males more susceptible to perinatal brain maldevelopment and although most abnormalities appear to have been resolved in juvenile animals, still permanent defects may be present, resulting in faulty neuronal circuits, and contribute to previously reported cognitive and behavioral phenotypes in adult BLOC-1-deficient mice.