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Research ArticleDevelopmentGenetics
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10.1172/jci.insight.161998
1Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
2University Lille, INSERM, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, FHU 1000 days for health, Lille, France.
3Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy.
4Department of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
5Department of Pediatrics, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
6Department of Pediatric Endocrinology and Diabetology, University Children’s Hospital, Zurich, Switzerland.
7Department of Endocrinology, Diabetology, and Metabolism, Lindenhofspital, Bern, Switzerland.
8Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, United Kingdom.
9Department of Experimental and Clinical Medicine, University of Florence, Italy.
Address correspondence to: Paolo Giacobini, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, 1 Place de Verdun, 59045, Lille, France. Phone: 33.320622060; Email: paolo.giacobini@inserm.fr. Or to: Valeria Vezzoli, Laboratory of Endocrine and Metabolic Research, Via Zucchi 18, 20095 Cusano Milanino, Milan, Italy. Phone: 39.02619112432; Email: valeriavezzoli@gmail.com.
Authorship note: MB, PG, and VV contributed equally to this work.
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1Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
2University Lille, INSERM, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, FHU 1000 days for health, Lille, France.
3Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy.
4Department of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
5Department of Pediatrics, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
6Department of Pediatric Endocrinology and Diabetology, University Children’s Hospital, Zurich, Switzerland.
7Department of Endocrinology, Diabetology, and Metabolism, Lindenhofspital, Bern, Switzerland.
8Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, United Kingdom.
9Department of Experimental and Clinical Medicine, University of Florence, Italy.
Address correspondence to: Paolo Giacobini, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, 1 Place de Verdun, 59045, Lille, France. Phone: 33.320622060; Email: paolo.giacobini@inserm.fr. Or to: Valeria Vezzoli, Laboratory of Endocrine and Metabolic Research, Via Zucchi 18, 20095 Cusano Milanino, Milan, Italy. Phone: 39.02619112432; Email: valeriavezzoli@gmail.com.
Authorship note: MB, PG, and VV contributed equally to this work.
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1Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
2University Lille, INSERM, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, FHU 1000 days for health, Lille, France.
3Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy.
4Department of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
5Department of Pediatrics, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
6Department of Pediatric Endocrinology and Diabetology, University Children’s Hospital, Zurich, Switzerland.
7Department of Endocrinology, Diabetology, and Metabolism, Lindenhofspital, Bern, Switzerland.
8Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, United Kingdom.
9Department of Experimental and Clinical Medicine, University of Florence, Italy.
Address correspondence to: Paolo Giacobini, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, 1 Place de Verdun, 59045, Lille, France. Phone: 33.320622060; Email: paolo.giacobini@inserm.fr. Or to: Valeria Vezzoli, Laboratory of Endocrine and Metabolic Research, Via Zucchi 18, 20095 Cusano Milanino, Milan, Italy. Phone: 39.02619112432; Email: valeriavezzoli@gmail.com.
Authorship note: MB, PG, and VV contributed equally to this work.
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1Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
2University Lille, INSERM, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, FHU 1000 days for health, Lille, France.
3Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy.
4Department of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
5Department of Pediatrics, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
6Department of Pediatric Endocrinology and Diabetology, University Children’s Hospital, Zurich, Switzerland.
7Department of Endocrinology, Diabetology, and Metabolism, Lindenhofspital, Bern, Switzerland.
8Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, United Kingdom.
9Department of Experimental and Clinical Medicine, University of Florence, Italy.
Address correspondence to: Paolo Giacobini, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, 1 Place de Verdun, 59045, Lille, France. Phone: 33.320622060; Email: paolo.giacobini@inserm.fr. Or to: Valeria Vezzoli, Laboratory of Endocrine and Metabolic Research, Via Zucchi 18, 20095 Cusano Milanino, Milan, Italy. Phone: 39.02619112432; Email: valeriavezzoli@gmail.com.
Authorship note: MB, PG, and VV contributed equally to this work.
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1Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
2University Lille, INSERM, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, FHU 1000 days for health, Lille, France.
3Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy.
4Department of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
5Department of Pediatrics, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
6Department of Pediatric Endocrinology and Diabetology, University Children’s Hospital, Zurich, Switzerland.
7Department of Endocrinology, Diabetology, and Metabolism, Lindenhofspital, Bern, Switzerland.
8Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, United Kingdom.
9Department of Experimental and Clinical Medicine, University of Florence, Italy.
Address correspondence to: Paolo Giacobini, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, 1 Place de Verdun, 59045, Lille, France. Phone: 33.320622060; Email: paolo.giacobini@inserm.fr. Or to: Valeria Vezzoli, Laboratory of Endocrine and Metabolic Research, Via Zucchi 18, 20095 Cusano Milanino, Milan, Italy. Phone: 39.02619112432; Email: valeriavezzoli@gmail.com.
Authorship note: MB, PG, and VV contributed equally to this work.
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1Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
2University Lille, INSERM, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, FHU 1000 days for health, Lille, France.
3Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy.
4Department of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
5Department of Pediatrics, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
6Department of Pediatric Endocrinology and Diabetology, University Children’s Hospital, Zurich, Switzerland.
7Department of Endocrinology, Diabetology, and Metabolism, Lindenhofspital, Bern, Switzerland.
8Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, United Kingdom.
9Department of Experimental and Clinical Medicine, University of Florence, Italy.
Address correspondence to: Paolo Giacobini, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, 1 Place de Verdun, 59045, Lille, France. Phone: 33.320622060; Email: paolo.giacobini@inserm.fr. Or to: Valeria Vezzoli, Laboratory of Endocrine and Metabolic Research, Via Zucchi 18, 20095 Cusano Milanino, Milan, Italy. Phone: 39.02619112432; Email: valeriavezzoli@gmail.com.
Authorship note: MB, PG, and VV contributed equally to this work.
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1Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
2University Lille, INSERM, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, FHU 1000 days for health, Lille, France.
3Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy.
4Department of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
5Department of Pediatrics, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
6Department of Pediatric Endocrinology and Diabetology, University Children’s Hospital, Zurich, Switzerland.
7Department of Endocrinology, Diabetology, and Metabolism, Lindenhofspital, Bern, Switzerland.
8Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, United Kingdom.
9Department of Experimental and Clinical Medicine, University of Florence, Italy.
Address correspondence to: Paolo Giacobini, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, 1 Place de Verdun, 59045, Lille, France. Phone: 33.320622060; Email: paolo.giacobini@inserm.fr. Or to: Valeria Vezzoli, Laboratory of Endocrine and Metabolic Research, Via Zucchi 18, 20095 Cusano Milanino, Milan, Italy. Phone: 39.02619112432; Email: valeriavezzoli@gmail.com.
Authorship note: MB, PG, and VV contributed equally to this work.
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1Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
2University Lille, INSERM, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, FHU 1000 days for health, Lille, France.
3Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy.
4Department of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
5Department of Pediatrics, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
6Department of Pediatric Endocrinology and Diabetology, University Children’s Hospital, Zurich, Switzerland.
7Department of Endocrinology, Diabetology, and Metabolism, Lindenhofspital, Bern, Switzerland.
8Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, United Kingdom.
9Department of Experimental and Clinical Medicine, University of Florence, Italy.
Address correspondence to: Paolo Giacobini, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, 1 Place de Verdun, 59045, Lille, France. Phone: 33.320622060; Email: paolo.giacobini@inserm.fr. Or to: Valeria Vezzoli, Laboratory of Endocrine and Metabolic Research, Via Zucchi 18, 20095 Cusano Milanino, Milan, Italy. Phone: 39.02619112432; Email: valeriavezzoli@gmail.com.
Authorship note: MB, PG, and VV contributed equally to this work.
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1Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
2University Lille, INSERM, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, FHU 1000 days for health, Lille, France.
3Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy.
4Department of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
5Department of Pediatrics, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
6Department of Pediatric Endocrinology and Diabetology, University Children’s Hospital, Zurich, Switzerland.
7Department of Endocrinology, Diabetology, and Metabolism, Lindenhofspital, Bern, Switzerland.
8Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, United Kingdom.
9Department of Experimental and Clinical Medicine, University of Florence, Italy.
Address correspondence to: Paolo Giacobini, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, 1 Place de Verdun, 59045, Lille, France. Phone: 33.320622060; Email: paolo.giacobini@inserm.fr. Or to: Valeria Vezzoli, Laboratory of Endocrine and Metabolic Research, Via Zucchi 18, 20095 Cusano Milanino, Milan, Italy. Phone: 39.02619112432; Email: valeriavezzoli@gmail.com.
Authorship note: MB, PG, and VV contributed equally to this work.
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1Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
2University Lille, INSERM, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, FHU 1000 days for health, Lille, France.
3Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy.
4Department of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
5Department of Pediatrics, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
6Department of Pediatric Endocrinology and Diabetology, University Children’s Hospital, Zurich, Switzerland.
7Department of Endocrinology, Diabetology, and Metabolism, Lindenhofspital, Bern, Switzerland.
8Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, United Kingdom.
9Department of Experimental and Clinical Medicine, University of Florence, Italy.
Address correspondence to: Paolo Giacobini, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, 1 Place de Verdun, 59045, Lille, France. Phone: 33.320622060; Email: paolo.giacobini@inserm.fr. Or to: Valeria Vezzoli, Laboratory of Endocrine and Metabolic Research, Via Zucchi 18, 20095 Cusano Milanino, Milan, Italy. Phone: 39.02619112432; Email: valeriavezzoli@gmail.com.
Authorship note: MB, PG, and VV contributed equally to this work.
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1Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
2University Lille, INSERM, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, FHU 1000 days for health, Lille, France.
3Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy.
4Department of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
5Department of Pediatrics, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
6Department of Pediatric Endocrinology and Diabetology, University Children’s Hospital, Zurich, Switzerland.
7Department of Endocrinology, Diabetology, and Metabolism, Lindenhofspital, Bern, Switzerland.
8Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, United Kingdom.
9Department of Experimental and Clinical Medicine, University of Florence, Italy.
Address correspondence to: Paolo Giacobini, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, 1 Place de Verdun, 59045, Lille, France. Phone: 33.320622060; Email: paolo.giacobini@inserm.fr. Or to: Valeria Vezzoli, Laboratory of Endocrine and Metabolic Research, Via Zucchi 18, 20095 Cusano Milanino, Milan, Italy. Phone: 39.02619112432; Email: valeriavezzoli@gmail.com.
Authorship note: MB, PG, and VV contributed equally to this work.
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1Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
2University Lille, INSERM, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, FHU 1000 days for health, Lille, France.
3Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy.
4Department of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
5Department of Pediatrics, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
6Department of Pediatric Endocrinology and Diabetology, University Children’s Hospital, Zurich, Switzerland.
7Department of Endocrinology, Diabetology, and Metabolism, Lindenhofspital, Bern, Switzerland.
8Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, United Kingdom.
9Department of Experimental and Clinical Medicine, University of Florence, Italy.
Address correspondence to: Paolo Giacobini, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, 1 Place de Verdun, 59045, Lille, France. Phone: 33.320622060; Email: paolo.giacobini@inserm.fr. Or to: Valeria Vezzoli, Laboratory of Endocrine and Metabolic Research, Via Zucchi 18, 20095 Cusano Milanino, Milan, Italy. Phone: 39.02619112432; Email: valeriavezzoli@gmail.com.
Authorship note: MB, PG, and VV contributed equally to this work.
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1Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
2University Lille, INSERM, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, FHU 1000 days for health, Lille, France.
3Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy.
4Department of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
5Department of Pediatrics, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
6Department of Pediatric Endocrinology and Diabetology, University Children’s Hospital, Zurich, Switzerland.
7Department of Endocrinology, Diabetology, and Metabolism, Lindenhofspital, Bern, Switzerland.
8Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, United Kingdom.
9Department of Experimental and Clinical Medicine, University of Florence, Italy.
Address correspondence to: Paolo Giacobini, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, 1 Place de Verdun, 59045, Lille, France. Phone: 33.320622060; Email: paolo.giacobini@inserm.fr. Or to: Valeria Vezzoli, Laboratory of Endocrine and Metabolic Research, Via Zucchi 18, 20095 Cusano Milanino, Milan, Italy. Phone: 39.02619112432; Email: valeriavezzoli@gmail.com.
Authorship note: MB, PG, and VV contributed equally to this work.
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1Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
2University Lille, INSERM, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, FHU 1000 days for health, Lille, France.
3Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy.
4Department of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
5Department of Pediatrics, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
6Department of Pediatric Endocrinology and Diabetology, University Children’s Hospital, Zurich, Switzerland.
7Department of Endocrinology, Diabetology, and Metabolism, Lindenhofspital, Bern, Switzerland.
8Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, United Kingdom.
9Department of Experimental and Clinical Medicine, University of Florence, Italy.
Address correspondence to: Paolo Giacobini, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, 1 Place de Verdun, 59045, Lille, France. Phone: 33.320622060; Email: paolo.giacobini@inserm.fr. Or to: Valeria Vezzoli, Laboratory of Endocrine and Metabolic Research, Via Zucchi 18, 20095 Cusano Milanino, Milan, Italy. Phone: 39.02619112432; Email: valeriavezzoli@gmail.com.
Authorship note: MB, PG, and VV contributed equally to this work.
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1Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
2University Lille, INSERM, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, FHU 1000 days for health, Lille, France.
3Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy.
4Department of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
5Department of Pediatrics, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
6Department of Pediatric Endocrinology and Diabetology, University Children’s Hospital, Zurich, Switzerland.
7Department of Endocrinology, Diabetology, and Metabolism, Lindenhofspital, Bern, Switzerland.
8Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, United Kingdom.
9Department of Experimental and Clinical Medicine, University of Florence, Italy.
Address correspondence to: Paolo Giacobini, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, 1 Place de Verdun, 59045, Lille, France. Phone: 33.320622060; Email: paolo.giacobini@inserm.fr. Or to: Valeria Vezzoli, Laboratory of Endocrine and Metabolic Research, Via Zucchi 18, 20095 Cusano Milanino, Milan, Italy. Phone: 39.02619112432; Email: valeriavezzoli@gmail.com.
Authorship note: MB, PG, and VV contributed equally to this work.
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1Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
2University Lille, INSERM, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, FHU 1000 days for health, Lille, France.
3Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy.
4Department of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
5Department of Pediatrics, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
6Department of Pediatric Endocrinology and Diabetology, University Children’s Hospital, Zurich, Switzerland.
7Department of Endocrinology, Diabetology, and Metabolism, Lindenhofspital, Bern, Switzerland.
8Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, United Kingdom.
9Department of Experimental and Clinical Medicine, University of Florence, Italy.
Address correspondence to: Paolo Giacobini, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, 1 Place de Verdun, 59045, Lille, France. Phone: 33.320622060; Email: paolo.giacobini@inserm.fr. Or to: Valeria Vezzoli, Laboratory of Endocrine and Metabolic Research, Via Zucchi 18, 20095 Cusano Milanino, Milan, Italy. Phone: 39.02619112432; Email: valeriavezzoli@gmail.com.
Authorship note: MB, PG, and VV contributed equally to this work.
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1Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
2University Lille, INSERM, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, FHU 1000 days for health, Lille, France.
3Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy.
4Department of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
5Department of Pediatrics, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
6Department of Pediatric Endocrinology and Diabetology, University Children’s Hospital, Zurich, Switzerland.
7Department of Endocrinology, Diabetology, and Metabolism, Lindenhofspital, Bern, Switzerland.
8Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, United Kingdom.
9Department of Experimental and Clinical Medicine, University of Florence, Italy.
Address correspondence to: Paolo Giacobini, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, 1 Place de Verdun, 59045, Lille, France. Phone: 33.320622060; Email: paolo.giacobini@inserm.fr. Or to: Valeria Vezzoli, Laboratory of Endocrine and Metabolic Research, Via Zucchi 18, 20095 Cusano Milanino, Milan, Italy. Phone: 39.02619112432; Email: valeriavezzoli@gmail.com.
Authorship note: MB, PG, and VV contributed equally to this work.
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Authorship note: MB, PG, and VV contributed equally to this work.
Published February 2, 2023 - More info
Published in Volume 8, Issue 5 on March 8, 2023
AbstractIn vertebrate species, fertility is controlled by gonadotropin-releasing hormone (GnRH) neurons. GnRH cells arise outside the central nervous system, in the developing olfactory pit, and migrate along olfactory/vomeronasal/terminal nerve axons into the forebrain during embryonic development. Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome are rare genetic disorders characterized by infertility, and they are associated with defects in GnRH neuron migration and/or altered GnRH secretion and signaling. Here, we documented the expression of the jagged-1/Notch signaling pathway in GnRH neurons and along the GnRH neuron migratory route both in zebrafish embryos and in human fetuses. Genetic knockdown of the zebrafish ortholog of JAG1 (jag1b) resulted in altered GnRH migration and olfactory axonal projections to the olfactory bulbs. Next-generation sequencing was performed in 467 CHH unrelated probands, leading to the identification of heterozygous rare variants in JAG1. Functional in vitro validation of JAG1 mutants revealed that 7 out of the 9 studied variants exhibited reduced protein levels and altered subcellular localization. Together our data provide compelling evidence that Jag1/Notch signaling plays a prominent role in the development of GnRH neurons, and we propose that JAG1 insufficiency may contribute to the pathogenesis of CHH in humans.
Graphical Abstract
Introduction
Reproduction and fertility in mammals are strictly dependent on a small population of hypothalamic neurons, the gonadotropin-releasing hormone (GnRH) neurons. GnRH-secreting neurons are unique neuroendocrine cells as they originate in the nasal placode, outside the central nervous system, during embryonic development, and migrate to the hypothalamus along the vomeronasal nerves (VNNs) and terminal nerves (TNs) (1). This process is evolutionarily conserved and follows a similar spatiotemporal pattern in all mammals (2), including humans (3, 4).
Any misfunction in the GnRH system leads to a human genetic disorder called congenital hypogonadotropic hypogonadism (CHH) (5). When CHH associates with hypo/anosmia, the disease is known as Kallmann syndrome (KS) (6, 7). In approximately 50% of affected individuals, no mutations can be identified in the known CHH genes, indicating that the genetics underlying CHH is still largely unknown (6, 8).
The GnRH migratory process is orchestrated by a plethora of factors, expressed along the GnRH migratory route, controlling cell signaling, adhesion, motility, and neurite and axonal elongation (8, 9).
It has been previously reported that Notch1 is expressed in the developing mouse olfactory epithelium from embryonic day 11 (10–12), corresponding to the beginning of the GnRH migratory process and olfactory axonal targeting (2). More recently, a group demonstrated an essential role for Notch1 in the development of the vomeronasal organ (13), where GnRH neurons are born (2, 4). However, the specific role of Notch signaling in the development of the GnRH system has not been investigated to our knowledge.
Four vertebrate Notch genes have been identified and are designated Notch1, Notch2, Notch3, and Notch4 (14–24). Mammalian Notch genes are widely expressed during embryonic development, suggesting that Notch regulates the differentiation of many different cell types.
Signaling is initiated when a Notch receptor on one cell interacts with Notch ligands, such as Delta-like ligand–1 (Dll-1), -3, and -4, and Serrate-like ligands (Jagged-1 and -2), on an adjacent cell (25).
Pathogenic allelic variants in JAG1 gene have been also described as causing Alagille syndrome, a rare autosomal dominant disease with characteristic liver, cardiac, eye, vertebral, and facial phenotypes (26).
In this study, we document for the first time to our knowledge the expression of JAG1, DLL1, and NOTCH1–4 genes in the human GnRH and olfactory/vomeronasal system during early fetal development.
We show that genetic invalidation of the zebrafish ortholog of JAG1 (jag1b) results in altered GnRH migration and olfactory axonal projections to the olfactory bulb. Moreover, we provide evidence that pharmacological invalidation of the Notch signaling pathway impairs the motility of a murine immortalized GnRH cell line and of human fetal GnRH-secreting neuroblasts representative of developing GnRH neurons (FNCB4) (27, 28).
The involvement of the JAG1 signaling pathway in GnRH development led to the identification of 9 heterozygous mutations in JAG1 among 467 patients with CHH. Collectively, this study identified a potentially novel embryonic role of Jag1/Notch signaling in the development of GnRH neurons and provided genetic evidence that disturbance of this signaling can contribute to CHH phenotype in humans.
ResultsJAG1 and NOTCH paralog mRNAs are expressed in and along the GnRH migratory route in human fetuses. Despite the presence of data regarding the expression of Notch signaling factors in the olfactory system of rodents (29), the expression of JAG1 signaling pathway in the developing olfactory, vomeronasal, and GnRH systems remains unknown. To fill this gap in knowledge, we investigated the expression of JAG1 and Notch paralogs’ transcripts (NOTCH1, NOTCH2, NOTCH3, NOTCH4), using multiplex fluorescence in situ hybridization (FISH), along the GnRH migratory route of human fetuses (Figure 1).
Figure 1JAG1 and Notch receptors are expressed in GnRH cells and in the olfactory/vomeronasal systems of human fetuses. (A) Schematic representation of a GW 8.5 human fetus head (coronal view). (B) Expression of JAG1 and NOTCH1-NOTCH4 in coronal section of the nasal compartment of a GW 8.5 human fetus. (C–H) High-power micrographs of FISH analysis for JAG1 and NOTCH1–NOTCH4 coupled with immunofluorescence for GnRH. Arrows in C point to GnRH-1 neurons expressing JAG1 and NOTCH1 transcripts. Arrows in D point to GnRH-1 neurons. Arrows in E point to GnRH-1 neurons expressing NOTCH1 and NOTCH2 transcripts. Arrowheads in F and G point to NOTCH4-expressing cells, and arrows highlight NOTCH3-expressing territories in the OE and VNO. Arrows in H point to GnRH-1 neurons expressing NOTCH3 transcripts and arrowhead depicts NOTCH4-expressing cells. OB, olfactory bulb; cx, cortex; sept, septum; OE, olfactory epithelium; VNO, vomeronasal organ; NS, nasal septum, HF, human fetus; GW, gestational weeks. Scale bars: 800 μm, B; 10 μm, C, E, and H; 200 μm, D; 100 μm, F and G. FISH experiments were replicated 3 times with similar results in n = 2 samples (GW 8.5 and GW 11).
Here, we report the expression of JAG1, NOTCH1, and NOTCH3 transcripts in the vomeronasal organ (VNO), in the developing olfactory epithelium (OE), as well as along chains of cells migrating across the nasal mesenchyme (Figure 1, A and B) in a fetus at GW 8.5. NOTCH2 and NOTCH4 expression was limited to the nasal tissue surrounding the VNO and OE (Figure 1B).
To assess the identity of cells expressing JAG1 and the Notch paralogs, we coupled FISH assay for JAG1 and Notch receptors with immunofluorescence for GnRH. We documented expression of JAG1 (Figure 1C), NOTCH1 (Figure 1, C and E), NOTCH2 (Figure 1, D and E), and NOTCH3 (Figure 1, F–H) transcripts in migratory GnRH neurons, whereas NOTCH4 was detectable in the nasal mesenchyme but not in GnRH neurons (Figure 1, F–H).
We next performed multiplex FISH experiments to assess JAG1 and NOTCH1–4 expression patterns in olfactory ensheathing cells (OECs), an important component of the nasal migratory mass (MM) (4), which contributes to the correct development of GnRH neurons (30). At GW 11, we detected large clusters of OECs migrating across the nasal region (Supplemental Figure 1; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.161998DS1) and expressing the OEC markers: low affinity nerve growth factor receptor (P75/NGFR), NGFR, and S100β. Our experiments showed that Jag1 and Notch1–3 transcripts were expressed in the OECs of the nasal compartment of human fetuses (Supplemental Figure 1, A–T), whereas NOTCH4 was expressed at low levels in the nasal mesenchyme but not in OECs (Supplemental Figure 1, U–Y).
Together, these data illustrate a strong expression of JAG1 and Notch receptors in GnRH neurons and in other cell types of the MM during early human fetal development.
JAG1 and DLL1 are expressed along the GnRH migratory route in human fetuses.
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