Gene regulatory networks controlling differentiation, survival, and diversification of hypothalamic Lhx6-expressing GABAergic neurons

Dong Won Kim,Sonia Hao Lin,Yi Stephanie Zhang,Hong Wang,Abhijith Bathini,Susan Lindtner,Bora Lee,Parris Whitney Washington,Seth Blackshaw,John L R Rubenstein,Tomomi Shimogori,Changyu Sun,Matthew P Brown,Kai Liu,Zoe Qianyi Wang

doi:10.1038/s42003-020-01616-7

Abstract

GABAergic neurons of the hypothalamus regulate many innate behaviors, but little is known about the mechanisms that control their development. We previously identified hypothalamic neurons that express the LIM homeodomain transcription factor Lhx6, a master regulator of cortical interneuron development, as sleep-promoting. In contrast to telencephalic interneurons, hypothalamic Lhx6 neurons do not undergo long-distance tangential migration and do not express cortical interneuronal markers such as Pvalb. Here, we show that Lhx6 is necessary for the survival of hypothalamic neurons. Dlx1/2, Nkx2-2, and Nkx2-1 are each required for specification of spatially distinct subsets of hypothalamic Lhx6 neurons, and that Nkx2-2+/Lhx6+ neurons of the zona incerta are responsive to sleep pressure. We further identify multiple neuropeptides that are enriched in spatially segregated subsets of hypothalamic Lhx6 neurons, and that are distinct from those seen in cortical neurons. These findings identify common and divergent molecular mechanisms by which Lhx6 controls the development of GABAergic neurons in the hypothalamus.

Highlights

GABAergic neurons of the hypothalamus regulate many innate behaviors, but little is known about the mechanisms that control their development
Lhx[6] neurons derived from Nkx2-2-expressing precursors are activated by sleep pressure. These findings identify mechanisms by which Lhx[6] can regulate the development of hypothalamic GABAergic neurons, and more broadly, how diverse subtypes of hypothalamic neurons can be generated during development
By E16.5, hypothalamic Lhx6-expressing neurons are observed in the zona incerta (ZI) and dorsomedial hypothalamus (DMH), in a pattern that broadly corresponds to the earlier intrahypothalamic diagonal (ID) domain, while expression in the posterior hypothalamus (PH) in turn broadly corresponds to the tuberomammillary terminal (TT) domain (Fig. 1F, G)

Summary

Introduction

GABAergic neurons of the hypothalamus regulate many innate behaviors, but little is known about the mechanisms that control their development. Previous work shows that hypothalamic GABAergic neuronal precursors first appear in a domain that separates the anterodorsal and posteroventral halves of the developing hypothalamus, and is delineated by expression of transcription factors that regulate the development of telencephalic GABAergic neurons, including Dlx1/2 and Arx[4,5,6,7,8]. Lhx[6] neurons derived from Nkx2-2-expressing precursors are activated by sleep pressure These findings identify mechanisms by which Lhx[6] can regulate the development of hypothalamic GABAergic neurons, and more broadly, how diverse subtypes of hypothalamic neurons can be generated during development

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Conclusion