Specialization of Gene Expression during Mouse Brain Development

Abstract

The transcriptome of the brain changes during development, reflecting processes that determine functional specialization of brain regions. We analyzed gene expression, measured using in situ hybridization across the full developing mouse brain, to quantify functional specialization of brain regions. Surprisingly, we found that during the time that the brain becomes anatomically regionalized in early development, transcription specialization actually decreases reaching a low, “neurotypic”, point around birth. This decrease of specialization is brain-wide, and mainly due to biological processes involved in constructing brain circuitry. Regional specialization rises again during post-natal development. This effect is largely due to specialization of plasticity and neural activity processes. Post-natal specialization is particularly significant in the cerebellum, whose expression signature becomes increasingly different from other brain regions. When comparing mouse and human expression patterns, the cerebellar post-natal specialization is also observed in human, but the regionalization of expression in the human Thalamus and Cortex follows a strikingly different profile than in mouse.

High-resolution mapping of transcriptional dynamics across tissue development reveals a stable mRNA–tRNA interface

“…As expected, between stages we saw large-scale changes in the expression of protein-coding genes known to have different functions during liver and brain development Kang et al 2011;Lee et al 2012;Liscovitch and Chechik 2013). For instance, Apob, which is the primary apolipoprotein carrying low-density lipoproteins, is steadily up-regulated during development; in contrast, alpha fetoprotein (Afp), the fetal version of serum albumin, is down-regulated through development and replaced by its adult counterpart ( Fig.…”

“…During early development, the embryonic liver is a haematopoetic organ; at birth, the neonatal liver becomes the primary metabolic and detoxification organ (Si-Tayeb et al 2010); at weaning, further metabolic pathways are up-regulated (Bohme et al 1983;Girard et al 1992). In the developing brain, coordinated gene expression changes in a heterogeneous collection of diverse cell types shape the functional specialization of specific regions in both embryonic and postnatal brains (Liscovitch and Chechik 2013;Sunkin et al 2013).…”

“…The direct interaction of these transcripts produced by Pol II and Pol III is a vital step in the flow of genetic information, in which the triplet codons in mRNAs are selectively identified by their counterpart tRNA anticodons to direct protein synthesis. To explore the largely unknown regulatory mechanisms active at this mRNA-tRNA interface, we exploited the rapid and extensive changes in the transcriptome occurring among different developmental stages of mammalian organogenesis (Kyrmizi et al 2006;Kang et al 2011;Lee et al 2012;Liscovitch and Chechik 2013;Sunkin et al 2013).…”

Pharmacologically Counteracting a Phenotypic Difference in Cerebellar GABAA Receptor Response to Alcohol Prevents Excessive Alcohol Consumption in a High Alcohol-Consuming Rodent Genotype

“…In all cases, statistical comparisons were two-tailed, and the significance threshold was set at p Ͻ 0.05. No statistical methods were used to predetermine sample sizes, but sample sizes for electrophysiology experiments are similar to those reported in the field (Hanchar et al, 2005;, and sample sizes for behavioral experiments are similar to those recently reported following bilateral microinjection of THIP into the nucleus accumbens shell in B6 mice (Ramaker et al, 2015).…”

“…Alcohol (ethanol) abuse is a leading cause of preventable death and disability (Lim et al, 2012), and accumulating evidence links the cerebellum to genetic risk for developing an alcohol use disorder (AUD) in humans (Schuckit, 1985;Hill et al, 2007;Hill, 2010;Herting et al, 2011) and excessive ethanol consumption in rodents (Gallaher et al, 1996;Yoneyama et al, 2008). We recently determined that physiologically relevant concentrations of etha-nol (9 -52 mM) differentially affect granule cell (GC) tonic GABA A receptor (GABA A R) currents, as a function of ethanol consumption phenotype Mohr et al, 2013).…”