Selenoprotein T Deficiency Leads to Neurodevelopmental Abnormalities and Hyperactive Behavior in Mice

Abstract

Selenoprotein T (SelT) is a newly discovered thioredoxin-like protein, which is abundantly but transiently expressed in the neural lineage during brain ontogenesis. Because its physiological function in the brain remains unknown, we developed a conditional knockout mouse line (Nes-Cre/SelT) in which SelT gene is specifically disrupted in nerve cells. At postnatal day 7 (P7), these mice exhibited reduced volume of different brain structures, including hippocampus, cerebellum, and cerebral cortex. This phenotype, which is observed early during the first postnatal week, culminated at P7 and was associated with increased loss of immature neurons but not glial cells, through apoptotic cell death. This phenomenon was accompanied by elevated levels of intracellular reactive oxygen species, which may explain the increased neuron demise and reduced brain structure volumes. At the second postnatal week, an increase in neurogenesis was observed in the cerebellum of Nes-Cre/SelT mice, suggesting the occurrence of developmental compensatory mechanisms in the brain. In fact, the brain volume alterations observed at P7 were attenuated in adult mice. Nevertheless, SelT mutant mice exhibited a hyperactive behavior, suggesting that despite an apparent morphological compensation, SelT deficiency leads to cerebral malfunction in adulthood. Altogether, these results demonstrate that SelT exerts a neuroprotective role which is essential during brain development, and that its loss impairs mice behavior.

A selenoprotein T‐derived peptide protects the heart against ischaemia/reperfusion injury through inhibition of apoptosis and oxidative stress

“…Together, these observations suggest that SelT expression is associated with cell plasticity, a process which requires increased metabolism and energy but which generates free radicals. Our recent studies performed in neuronal cells showed that SelT is required for oxidative stress tolerance and that its biosynthesis is coupled to mitochondrial function during differentiation . Therefore, SelT expression during cardiac tissue ontogenesis is likely involved in cardiomyocyte protection and differentiation.…”

“…Several selenoproteins are highly expressed during development, and their loss has been associated with major anatomical alterations and functional defects in rodents . In particular, selenoprotein T (SelT or SELENOT) is a key thioredoxin‐like enzyme present in the endoplasmic reticulum, which is essential at early stage of mouse development . SelT is highly expressed in most embryonic organs, but declines gradually as the organs develop, to disappear in most adult tissues except the endocrine glands .…”

“…16,17 In particular, selenoprotein T (SelT or SELE-NOT) is a key thioredoxin-like enzyme present in the endoplasmic reticulum, 18,19 which is essential at early stage of mouse development. 20,21 SelT is highly expressed in most embryonic organs, but declines gradually as the organs develop, to disappear in most adult tissues except the endocrine glands. 15,19,22 Targeted inactivation of SelT in pancreatic b-cells resulted in a reduction in pancreatic islet size and impaired glucose tolerance, thus indicating a possible defect in cell commitment to b-cell lineage.…”

Why 21? The significance of selenoproteins for human health revealed by inborn errors of metabolism

“…The so‐far elusive other selenoprotein essential for neurons may be selenoprotein T (SelT) (61). SelT is an ER‐ resident selenoprotein with a thioredoxin‐like structure and activity.…”

“…How exactly its deficiency impairs neurologic function is currently not known. A neural-specific knockout of SelT leads to hyperactive behavior and moderate signs of cell death during brain development, but epilepsy, loss of PV interneurons, and overt degeneration of cortical or hippocampal neurons have not been reported (61).…”