Transcriptomics of the late gestation ovine fetal brain: modeling the co-expression of immune marker genes

Abstract

Background: Major changes in gene expression occur in the fetal brain to modulate the function of this organ postnatally. Thus, factors can alter the genomics of the fetal brain, predisposing to neurological disorders later in life. We hypothesized that the physiological dynamics of the immune system transcriptome of the fetal brain during the last stage of gestation will reveal patterns of immune function and development in the developing brain. In this study we applied weighted gene co-expression analysis of microarrays performed on ovine fetal brain samples, to model the changes in gene expression throughout the second half of gestation.

Results: Clusters of co-expressed genes that strongly increase in expression toward the first day of extra-uterine life are related to the hematopoietic lineage, while activation of immune pathways is induced after birth. Moreover, the pattern of gene expression suggests induction of tolerance mechanisms, probably necessary to protect highly produced proteins--such as myelin basic protein--from an autoimmune attack.

Conclusions: This study provides insight into the dramatic changes in gene expression that take place in the brain during the fetal life, especially during the last stage of gestation, and suggests that the immune system may have an important role in maturation of the fetal brain, which if disrupted or altered, could have negative consequences in postnatal life.

Figure 1

Networks composed by nodes (genes) related to the hematopoiesis in the ovine fetal brain. Black nodes are genes belonging to the top positively correlated module for each brain region. Grey nodes are genes inferred by the GeneMania plugin. Brain regions are cortex (A), brainsteam (B), hippocampus (C) and hypothalamus (D).

Figure 2

The nodes (genes) of the merged network represent markers for immune cells of the hematopoietic lineage. HSC, Hematopoietic stem cell; MPP, multipotent progenitor; LMPP, lymphoid-primed multipotent progenitor; CLP, common lymphoid progenitor; GMP, granulocyte macrophage progenitor. Hematopoiesis figure reprinted with permission from the Nature Publishing Group. (Source: Welinder and Murre, 2011. Ldb1, a new guardian of hematopoietic stem cell maintenance. Nature Immunology, Vol 12:2. Figure 1, page 113).

Figure 3

Trajectories of gene expression for immune related genes. (A) Genes related with the hematopoietic lineage are increased in expression along fetal age and first day of extrauterine life –day 160-(solid line, filled circles). Genes related with immune system activation are strongly induced after birth (dashed line, open diamond). (B) Opposite trajectory expression of CD24 gene (dashed line, open diamond) and MBP gene (solid line, filled circle).