Ectopic expression of <i>Irx3</i> and <i>Irx5</i> in the paraventricular nucleus of the hypothalamus contributes to defects in <i>Sim1</i> haploinsufficiency.
basic_science · Level V
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- Record sourced from PubMed, PMID 34705510.
- Also identified by DOI 10.1126/sciadv.abh4503 and PMC identifier 8550250.
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Abstract
The paraventricular nucleus of the hypothalamus (PVH) contains a heterogeneous cluster of <i>Sim1</i>-expressing neurons critical for feeding regulation. <i>Sim1</i> haploinsufficiency results in hyperphagic obesity with disruption of PVH neurons, yet the molecular profiles of PVH neurons and the mechanism underlying the defects of <i>Sim1</i> haploinsufficiency are not well understood. By single-cell RNA sequencing, we identified two major populations of <i>Sim1</i><sup>+</sup> PVH neurons, which are differentially affected by <i>Sim1</i> haploinsufficiency. The <i>Iroquois</i> homeobox genes <i>Irx3</i> and <i>Irx5</i> have been implicated in the hypothalamic control of energy homeostasis. We found that <i>Irx3</i> and <i>Irx5</i> are ectopically expressed in the <i>Sim1</i><sup>+</sup> PVH cells of <i>Sim1</i><sup>+/−</sup> mice. By reducing their dosage and PVH-specific deletion of <i>Irx3</i>, we demonstrate that misexpression of <i>Irx3</i> and <i>Irx5</i> contributes to the defects of <i>Sim1</i><sup>+/−</sup> mice. Our results illustrate abnormal hypothalamic activities of <i>Irx3</i> and <i>Irx5</i> as a central mechanism disrupting PVH development and feeding regulation in <i>Sim1</i> haploinsufficiency.