Deciphering the Regulatory Role of TLX in Adult Neurogenesis

Review of “Impaired generation of mature neurons due to extended expression of Tlx by repressing Sox2 transcriptional activity” from STEM CELLS by Stuart P. Atkinson

The neural stem cells (NSCs) present in the subventricular zone (SVZ) and the subgranular zone (SGZ) of the adult rodent brain display the capacity to self-renew and differentiate [1, 2]. Previous studies have identified  Tailless (TLX - also known as NR2E1) as a fundamental regulator of adult NSCs homeostasis and neurogenesis. Indeed, the inactivation of TLX in adult SVZ NSCs leads to a complete loss of neurogenesis [3, 4], while the conditional disruption of TLX in the SGZ reduces cognitive aptitude and induces abnormal behavior [5, 6].

To investigate the molecular mechanisms regulating the precise spatiotemporally expression of TLX in adult brain NSCs, researchers led by Ying Wang (Nanjing Medical University, Nanjing, China) recently generated a TLX gain-of-expression transgenic mouse model that allows the extended expression of TLX in NSCs and their progeny. In their new STEM CELLS article, Wang et al. now describe the importance of TLX regulation to NSC behavior and provide a basis for the further understanding of adult neurogenesis and the development of treatment strategies for neurological disorders [7].

The authors discovered that the prolonged expression of TLX impaired the generation of mature neurons (but did not affect glial/oligodendroglial differentiation) in the adult SVZ (in both in vitro and in vivo models) and the SGZ (in vivo) by inhibiting the endogenous expression of SOX2 by directly binding to the gene promoter region. TLX binding induced the deposition of repressive histone modifications (H3K27me3) and inhibited the deposition of a permissive histone modification (H3K4me3). These chromatin modifications lead to the formation of a more compact, less accessible chromatin environment surrounding affected regions, which generally correlates to the inhibited transcription of the associate gene.

Of note, the study also linked the TLX-mediated inhibition of SGZ neurogenesis with a reduction in learning and memory ability in affected mice. In confirmation of a link between TLX and SOX2, the study established that the forced expression of SOX2 partially rescued the neuron maturation defects observed following prolonged TLX expression.

Overall, the description of the TLX-SOX2 regulatory pathway in NSCs provides new insight into the control of adult neurogenesis and may pave the way for novel therapies for a range of neurological diseases and disorders.

For more on how deciphering the complex regulatory pathways governing adult neurogenesis may support the development of new therapies, stay tuned to the Stem Cells Portal!

References

1. Obernier K and Alvarez-Buylla A, Neural stem cells: origin, heterogeneity and regulation in the adult mammalian brain. Development 2019;146.
2. Ortiz-Álvarez G, Daclin M, Shihavuddin A, et al., Adult Neural Stem Cells and Multiciliated Ependymal Cells Share a Common Lineage Regulated by the Geminin Family Members. Neuron 2019;102:159-172.e7.
3. Liu H-K, Belz T, Bock D, et al., The nuclear receptor tailless is required for neurogenesis in the adult subventricular zone. Genes & Development 2008;22:2473-2478.
4. Liu H-K, Wang Y, Belz T, et al., The nuclear receptor tailless induces long-term neural stem cell expansion and brain tumor initiation. Genes & Development 2010;24:683-695.
5. Zhang C-L, Zou Y, He W, et al., A role for adult TLX-positive neural stem cells in learning and behaviour. Nature 2008;451:1004-1007.
6. Murai K, Qu Q, Sun G, et al., Nuclear receptor TLX stimulates hippocampal neurogenesis and enhances learning and memory in a transgenic mouse model. Proceedings of the National Academy of Sciences 2014;111:9115.
7. Wang Y, Li B, Dong L, et al., Impaired generation of mature neurons due to extended expression of Tlx by repressing Sox2 transcriptional activity. STEM CELLS 2021;39:1520-1531.