PUBLICATION

Islet 1 specifies the identity of hypothalamic melanocortin neurons and is critical for normal food intake and adiposity in adulthood

Authors

Nasif, S., de Souza, F.S., González, L.E., Yamashita, M., Orquera, D.P., Low, M.J., Rubinstein, M.

ID

ZDB-PUB-150401-3

Date

2015

Source

Proceedings of the National Academy of Sciences of the United States of America 112(15): E1861-70 (Journal)

Registered Authors

Keywords

Isl1, hypothalamus, melanocortin, obesity, pomc

MeSH Terms

Obesity/genetics
Obesity/physiopathology
Neurons/cytology
Neurons/metabolism*
Adiposity/genetics
Adiposity/physiology*
Male
Protein Binding
Pro-Opiomelanocortin/genetics
Pro-Opiomelanocortin/metabolism*
Cell Differentiation/genetics
Cell Differentiation/physiology
Hyperphagia/genetics
Hyperphagia/physiopathology
Base Sequence
LIM-Homeodomain Proteins/genetics
LIM-Homeodomain Proteins/metabolism*
Female
Transcription Factors/genetics
Transcription Factors/metabolism*
Zebrafish/embryology
Zebrafish/metabolism
Animals
Mice, Knockout
Reverse Transcriptase Polymerase Chain Reaction
Hypothalamus/cytology
Hypothalamus/embryology
Hypothalamus/metabolism
Gene Expression Regulation, Developmental
Eating/genetics
Eating/physiology*
Sequence Homology, Nucleic Acid
Gene Knockdown Techniques
Molecular Sequence Data
Microscopy, Fluorescence
Mice, Transgenic

(all 36)

PubMed

25825735 Full text @ Proc. Natl. Acad. Sci. USA

Abstract

Food intake and body weight regulation depend on proper expression of the proopiomelanocortin gene (Pomc) in a group of neurons located in the mediobasal hypothalamus of all vertebrates. These neurons release POMC-encoded melanocortins, which are potent anorexigenic neuropeptides, and their absence from mice or humans leads to hyperphagia and severe obesity. Although the pathophysiology of hypothalamic POMC neurons is well understood, the genetic program that establishes the neuronal melanocortinergic phenotype and maintains a fully functional neuronal POMC phenotype throughout adulthood remains unknown. Here, we report that the early expression of the LIM-homeodomain transcription factor Islet 1 (ISL1) in the developing hypothalamus promotes the terminal differentiation of melanocortinergic neurons and is essential for hypothalamic Pomc expression since its initial onset and throughout the entire lifetime. We detected ISL1 in the prospective hypothalamus just before the onset of Pomc expression and, from then on, Pomc and Isl1 coexpress. ISL1 binds in vitro and in vivo to critical homeodomain binding DNA motifs present in the neuronal Pomc enhancers nPE1 and nPE2, and mutations of these sites completely disrupt the ability of these enhancers to drive reporter gene expression to hypothalamic POMC neurons in transgenic mice and zebrafish. ISL1 is necessary for hypothalamic Pomc expression during mouse and zebrafish embryogenesis. Furthermore, conditional Isl1 inactivation from POMC neurons impairs Pomc expression, leading to hyperphagia and obesity. Our results demonstrate that ISL1 specifies the identity of hypothalamic melanocortin neurons and is required for melanocortin-induced satiety and normal adiposity throughout the entire lifespan.

Genes / Markers

Figures

Show all Figures

Expression

Gene	Fish	Conditions	Stage	Qualifier	Anatomy	Assay	Figure
agrp	AB	standard conditions	Protruding-mouth		hypothalamus	ISH	Fig. 7
agrp	AB + MO4-isl1a	standard conditions	Protruding-mouth		hypothalamus	ISH	Fig. 7
EGFP	zf597Tg	standard conditions	Protruding-mouth		hypophysis	IFL	Fig. S8
EGFP	zf597Tg	standard conditions	Protruding-mouth		hypothalamus	IFL	Fig. S8
EGFP	zf597Tg + MO4-isl1a	standard conditions	Protruding-mouth		hypophysis	IFL	Fig. S8
EGFP	zf597Tg + MO4-isl1a	standard conditions	Protruding-mouth	Not Detected	hypothalamus	IFL	Fig. S8
pomca	AB	standard conditions	Protruding-mouth		hypothalamus	ISH	Fig. 7
pomca	AB + MO4-isl1a	standard conditions	Protruding-mouth	Not Detected	hypothalamus	ISH	Fig. 7
pomcb	AB	standard conditions	Protruding-mouth		preoptic area	ISH	Fig. 7
pomcb	AB + MO4-isl1a	standard conditions	Protruding-mouth		preoptic area	ISH	Fig. 7

1 - 10 of 10

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
AB + MO4-isl1a	standard conditions	Protruding-mouth	heart development disrupted, abnormal	Fig. 7
AB + MO4-isl1a	standard conditions	Protruding-mouth	heart edematous, abnormal	Fig. 7
AB + MO4-isl1a	standard conditions	Protruding-mouth	hypothalamus neuron decreased amount, abnormal	Fig. 7
AB + MO4-isl1a	standard conditions	Protruding-mouth	post-vent region curved ventral, abnormal	Fig. 7
AB + MO4-isl1a	standard conditions	Protruding-mouth	whole organism decreased size, abnormal	Fig. 7

1 - 5 of 5

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
zf597Tg	Tg(Mmu.Pomc-pomca:pomca-EGFP)	Transgenic Insertion

Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
isl1a	MO4-isl1a	MRPHLNO

Fish

Fish
AB
AB + MO4-isl1a
zf597Tg
zf597Tg + MO4-isl1a

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP

Mapping

Nasif et al., 2015 ZDB-PUB-150401-3 PMID:25825735

Islet 1 specifies the identity of hypothalamic melanocortin neurons and is critical for normal food intake and adiposity in adulthood

Nasif et al., 2015

ZDB-PUB-150401-3
PMID:25825735