👤 Matthijs Verhage

The melanocortin-3 receptor (MC3R) and the melanocortin-4 receptor (MC4R), both expressed in hypothalamic nuclei, are key downstream effectors of leptin signaling and play important roles in energy homeostasis. While pathogenic variants in the MC4R gene represent the most common cause of monogenic obesity, the clinical significance of MC3R variants is less clear. MC4R localizes to the primary cilium, a sensory organelle present on nearly all human cells. To better understand the pathophysiological mechanisms of MC3R variants, we investigated whether MC3R localizes to the primary cilium and assessed the impact of rare MC3R variants identified in individuals with obesity on ciliary expression. Using human RPE cells, human NGN2-induced iNeurons, and primary mouse hypothalamic neurons, we found that, in contrast to MC4R, neither wild type MC3R nor rare MC3R variants localized specifically to the primary cilium in vitro in any cell type, including hypothalamic neurons. These findings suggest that MC3R and MC4R may utilize distinct signaling pathways or that additional factors, such as accessory proteins, are required for MC3R targeting to primary cilia in vivo. Further studies are needed to clarify the role of MC3R variants in monogenic obesity and their broader implications for human disease. Show less

Human excitatory neurons programmed through neurogenin-2 (NGN2) overexpression are widely used to model brain disorders in vitro. Although growth factors (GFs) such as BDNF, GDNF, NT3 and CNTF are commonly included in differentiation protocols, their individual and combined effects on neuronal survival, morphology and function remain insufficiently characterized. Here, we systematically examined the impact of these GFs, alone or in combination, on the development and maturation of NGN2-neurons. We also compare network activity of neurons maintained in Neurobasal medium (NBM) versus BrainPhys (PB). We show that BDNF or GDNF alone were sufficient to support neuronal survival and morphological complexity, whereas functional maturation, including network activity, required CNTF. Furthermore, BP supported neuronal development and function comparable to NBM, provided appropriate supplementation. Together, our results show that CNTF in combination with either BDNF or GDNF provides the most effective support for both structural and functional maturation of NGN2-neurons derived from male induced pluripotent stem cells (iPSCs). These findings offer a better understanding of how GF supplementation shapes neuronal development and provide a framework for optimizing human neuron culture conditions in disease modeling and drug discovery. Show less

Multiple lines of evidence suggest that fatty acids (FA) play an important role in cognitive function. However, little is known about the functional genetic pathways involved in cognition. The main goals of this study were to replicate previously reported interaction effects between breast feeding (BF) and FA desaturase (FADS) genetic variation on IQ and to investigate the possible mechanisms by which these variants might moderate BF effect, focusing on brain expression. Using a sample of 534 twins, we observed a trend in the moderation of BF effects on IQ by FADS2 variation. In addition, we made use of publicly available gene expression databases from both humans (193) and mice (93) and showed that FADS2 variants also correlate with FADS1 brain expression (P-value<1.1E-03). Our results provide novel clues for the understanding of the genetic mechanisms regulating FA brain expression and improve the current knowledge of the FADS moderation effect on cognition. Show less