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

The function(s) of the Biogenesis of Lysosome-related Organelles Complex 1 (BLOC-1) during brain development is hitherto 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 GLAST. 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 abse..., Histomorphometrical and Immunohistochemical Analyses

P1 male and female, and P45 male, wild-type and pallid mice were anesthetized with isoflurane (30-32%) and transcardially perfused with phosphate-buffered saline (PBS, 0.1 M, pH 7.4) containing 4% (w/v) paraformaldehyde (Electron Microscopy Sciences, Hatfield, PA). The brains were rapidly dissected out, post-fixed overnight in 4% (w/v) paraformaldehyde at 4°C, and cryoprotected in 15% (w/v) sucrose. Coronal sections were cut on a cryostat (Leica, Buffalo Grove, IL) collected sequentially, and paired along the anterior-posterior axis before further processing.

For Nissl Staining, coronal brain sections (20 μm) were stained with a 1% (w/v) cresyl violet (Sigma-Aldrich Corp., St. Louis, MO) solution as previously reported (Lee et al., 2018). Photographs were acquired on a Zeiss Axioskop equipped with a Zeiss colour or monochrome Axiocam using the AxioVision software (Zeiss, Pleasanton, CA) and used to determine the thickness of the...,