Related Experiment Video
Updated: Mar 8, 2026
Generation of iPSC-derived Human Brain Organoids to Model Early Neurodevelopmental Disorders
Published on: April 14, 2017
PC1/3 Deficiency Impacts Pro-opiomelanocortin Processing in Human Embryonic Stem Cell-Derived Hypothalamic Neurons
Liheng Wang1, Lina Sui2, Sunil K Panigrahi3
1Division of Molecular Genetics, Department of Pediatrics and Naomi Berrie Diabetes Center, College of Physicians and Surgeons, Columbia University, 1150 St. Nicholas Avenue, Room 620A, New York, NY 10032, USA; Department of Medicine and Naomi Berrie Diabetes Center, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Human pluripotent stem cells model PCSK1 deficiency, a cause of severe obesity. This study reveals obesity in PCSK1 deficiency may not stem from alpha-MSH deficiency, offering new insights into metabolic disease.
Area of Science:
- Neuroscience
- Stem Cell Biology
- Genetics
Background:
- Proprotein convertase subtilisin/kexin type 1 (PCSK1), also known as PC1/3, is crucial for prohormone processing in neuroendocrine tissues.
- PCSK1 deficiency causes severe obesity, but the underlying mechanisms remain incompletely understood.
- Human pluripotent stem cells offer a promising model for studying neuroendocrine function and disease.
Purpose of the Study:
- To investigate the role of PCSK1 in prohormone processing using human embryonic stem cell (hESC)-derived hypothalamic neurons.
- To model monogenic severe obesity caused by PCSK1 deficiency in vitro.
- To elucidate the mechanisms linking PCSK1 deficiency to obesity.
Main Methods:
- Generation of PCSK1-deficient hESC lines using short hairpin RNA (shRNA) and CRISPR-Cas9 gene editing.
- Differentiation of hESCs into hypothalamic neurons.
- Analysis of pro-opiomelanocortin (POMC) processing and related peptide levels.
- Assessment of melanocortin receptor and PRCP expression.
- Measurement of adrenocorticotropic hormone secretion.
Main Results:
- PCSK1 deficiency in hESC-derived neurons led to increased unprocessed POMC and altered ratios of processed POMC-derived peptides.
- These findings phenocopied POMC processing defects observed in PCSK1-deficient models and patients.
- PC1/3 deficiency was associated with altered expression of melanocortin receptors and PRCP, and reduced ACTH secretion.
- Obesity in PCSK1 deficiency may not be primarily driven by a deficiency in alpha-melanocyte stimulating hormone (αMSH).
Conclusions:
- hESC-derived hypothalamic neurons provide a valuable model for studying PCSK1 deficiency and its impact on neuroendocrine function.
- The study challenges the prevailing hypothesis that αMSH deficiency is the primary driver of obesity in PCSK1 deficiency.
- These findings open new avenues for understanding the complex pathophysiology of obesity related to prohormone processing defects.
More Related Videos
12:01Induction of Protein Deletion Through In Utero Electroporation to Define Deficits in Neuronal Migration in Transgenic Models
Published on: January 12, 2015
14:192D and 3D Human Induced Pluripotent Stem Cell-Based Models to Dissect Primary Cilium Involvement during Neocortical Development
Published on: March 25, 2022