Abstract
Dopaminergic (DA) neurons in the arcuate nucleus (ARC) of the hypothalamus play essential roles in the secretion of prolactin and the regulation of energy homeostasis. However, the gene regulatory network responsible for the development of the DA neurons remains poorly understood. Here we report that the transcription factor special AT-rich binding protein 2 (Satb2) is required for the development of ARC DA neurons. Satb2 is expressed in a large proportion of DA neurons without colocalization with proopiomelanocortin (POMC), orexigenic agouti-related peptide (AgRP), neuropeptide-Y (NPY), somatostatin (Sst), growth hormone-releasing hormone (GHRH), or galanin in the ARC. Nestin-Cre;Satb2flox/flox (Satb2 CKO) mice show a reduced number of ARC DA neurons with unchanged numbers of the other types of ARC neurons, and exhibit an increase of serum prolactin level and an elevated metabolic rate. The reduction of ARC DA neurons in the CKO mice is observed at an embryonic stage and Dlx1 is identified as a potential downstream gene of Satb2 in regulating the development of ARC DA neurons. Together, our study demonstrates that Satb2 plays a critical role in the gene regulatory network directing the development of DA neurons in ARC.
Highlights
Hypothalamus, in particular the arcuate nucleus (ARC), is critical for the regulation of feeding and metabolism [1]
Calorimetry was performed for 24 h spanning both the dark (12 h) and light (12 h) cycles. c respiratory exchange ratio (RER) was measured based on the oxygen and carbon dioxide data obtained by indirect calorimetry and showed no significant difference between control and special AT-rich binding protein 2 (Satb2) CKO mice. d The energy expenditure data averaged for 24 h are comparable between control and Satb2 CKO mice
GAD67+, Sst+, growth hormone-releasing hormone (GHRH)+, and Galanin+ neurons remain unchanged in ARC of Satb2 CKO mice We have shown that the development of DA neurons is affected in Satb2 CKO mice with unchanged NPY+ and POMC+ populations
Summary
Hypothalamus, in particular the arcuate nucleus (ARC), is critical for the regulation of feeding and metabolism [1]. The ARC contains other types of neurons, such as those expressing somatostatin (Sst), growth hormone-releasing hormone (GHRH), galanin, and dopamine, and many non-POMC neurons contain and release inhibitory neurotransmitter γ-aminobutyric acid (GABA) [3]. One of the well-known physiological roles of ARC DA neurons is to suppress the secretion of prolactin from prolactin-producing cells (lactotrophs) in the anterior pituitary gland through activating dopamine receptor 2 (D2) receptors. The development of ARC DA neurons was impaired, with normal appearance of other neuron types expressing POMC, AgRP/NPY, GAD67, Sst, GHRH, and Galanin, indicating a specific role of Satb in the development of ARC DA neurons. Official journal of CDDpress revealed that Dlx is likely to be a downstream gene of Satb in DA neurons are selectively reduced in ARC of adult Satb CKO regulating the development of ARC DA neurons.
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