Thyroid Hormone Signaling Acts as a Neurogenic Switch by Repressing Sox2 in the Adult Neural Stem Cell Niche

Abstract

The subventricular zone (SVZ) neural stem cell niche contains mixed populations of stem cells, transit-amplifying cells, and migrating neuroblasts. Deciphering how endogenous signals, such as hormones, affect the balance between these cell types is essential for understanding the physiology of niche plasticity and homeostasis. We show that Thyroid Hormone (T(3)) and its receptor, TRα1, are directly involved in maintaining this balance. TRα1 is expressed in amplifying and migrating cells. In vivo gain- and loss-of-function experiments demonstrate first, that T(3)/TRα1 directly repress Sox2 expression, and second, that TRα1 overexpression in the niche favors the appearance of DCX+ migrating neuroblasts. Lack of TRα increases numbers of SOX2+ cells in the SVZ. Hypothyroidism increases proportions of cells in interphase. Thus, in the adult SVZ, T(3)/TRα1 together favor neural stem cell commitment and progression toward a migrating neuroblast phenotype; this transition correlates with T(3)/TRα1-dependent transcriptional repression of Sox2.

Thyroid Hormone-Otx2 Signaling Is Required for Embryonic Ventral Midbrain Neural Stem Cells Differentiated into Dopamine Neurons

“…As demonstrated by our group and others, the thyroid hormone is known to be a critical factor in promoting the neural differentiation of NSCs, both in the early stage of embryonic cortex and in the adult hippocampus [7,9,11]. These results suggested that the thyroid hormone probably acts in a different manner during different developmental stages.…”

“…The effects of the thyroid hormone on NSCs in the adult hippocampus and the subventricular zone have also been well described [10,11]. However, the role of the thyroid hormone on NSC biology in the midbrain remains unclear.…”

The Epigenetic Modifier Ubiquitin-specific Protease 22 (USP22) Regulates Embryonic Stem Cell Differentiation via Transcriptional Repression of Sex-determining Region Y-box 2 (SOX2)

“…Perhaps the strongest evidence for H2B as the relevant USP22 substrate at the Sox2 locus comes from our observation that blocking H2B ubiquitylation by depleting ESCs of the H2B E3 ligase RNF20 results in decreased SOX2 expression. From a developmental standpoint, USP22-mediated repression of Sox2 may contribute to the embryonic lethality observed in USP22 null mice at day 9.5, a stage when Sox2 repression is critical for the differentiation of neural stem cells in the closing neuropore and developing brain (26,38,40,71,72).…”

Thyroid Hormone Signaling and Adult Neurogenesis in Mammals

“…Recently, T 3 was demonstrated to exert critical roles in cell proliferation and NSC commitment toward neuroblasts in both the rodent SVZ and SGZ in vivo (15, 16). T 3 acts on transcription through nuclear receptors, Thyroid Hormone Receptors (TRs).…”

“…In vertebrates, different isoforms derive from the Thra (TRα2 and TRα2) and Thrb (TRβ1 and TRβ2) genes. The adult hippocampus expresses TRα1, TRβ1, and β2 isoforms (16, 34), whereas only TRα1 is expressed in the adult mouse SVZ (13, 15). …”