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FLASH GENE

Symbol

ISL1

contributors: shn/npt - updated : 31-05-2017

HGNC name	ISL LIM homeobox 1
HGNC id	6132

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	11.61 kb     6 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

provisional

Map	ISL1 gene has been mapped by linkage analysis on 5q

regionally located

cen - D5S466 - D5S822 - ISL1 - D5S660 - D5S2035 - qter

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_002202 6 - 2729 NP_002193 36.7 349 mouse tooth and mandibular development Mitsiadis et al, 2003

EXPRESSION

Type	restricted

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Endocrine adrenal gland medulla       Nervous brain diencephalon epithalamus pineal gland     brain basal nuclei striatum     Homo sapiens Fetal   ganglia sensory ganglia dorsal root     Reproductive male system testis       Visual eye

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial secretory glandular endocrine   Epithelial sensory visual inner nuclear layer   Nervous autonomous       Nervous central       Nervous peripherous

cells

System Cell Pubmed Species Stage Rna symbol Nervous neuron

cell lineage

cell lines

fluid/secretion

at STAGE

Text	In embryonic mice, sensory neurons coexpress the pan-sensory homeodomain ranscription factors Islet1 and Brn3a

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	two cysteine-rich (LIM) domain
	an helix-turn-helix DNA binding domain

HOMOLOGY

interspecies	ortholog to murine, Isl1
	ortholog to isl1, Xenopus (Silurana) tropicalis
	ortholog to isl-1, Rattus norvegicus
	ortholog to islet1, Danio rerio

intraspecies

homolog to Isl2, Lim1 and Lim2, Lhx6 and Lhx7

Homologene

FAMILY

LIM-homeo domain family of transcription factors

CATEGORY

regulatory , DNA associated , transcription factor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm
	intracellular,nucleus

basic FUNCTION	plays an important role in the embryogenesis of pancreatic islets of Langerhans
	required for proliferation, survival, and migration of recently defined second heart field progenitors
	LIM homeodomain protein that plays an important role in insulin gene transcriptional activation and islet cell formation and may be required for motor neuron generation
	In the spinal cord, Islet1 has an essential role in the early survival of motor neurons
	Islet1 is required to terminate the expression of key
	regulators of the neurogenic phase of sensory development
	requirement in the development of restricted telencephalic cholinergic neurons and the development of cholinergic neurons in anatomically disparate sites is linked to ISL1 function (Elshatory 2008)
	ISL1 and POU4F2 concurrently bind to and synergistically regulate the expression of a common set of retinal ganglion cells-specific genes
	essential for pancreatic islet cell and dorsal mesenchyme development
	transcription factor that marks cardiac progenitor cells and generates diverse multipotent cardiovascular cell lineages
	plays essential roles during embryogenesis
	required for the survival and specification of spinal cord motor neurons, and required for survival of cranial ganglia neurons
	required for the nuclear accumulation of CTNNB and hence for activation of the CTNNB pathway, and the CTNNB pathway maintains ISL1 expression
	hindlimb-specific transcriptional regulator of initiation
	transcription factor that has been associated with the multipotency of human cardiac progenitors
	is required for the normal expression of Ikaros in striatal neuron progenitors
	ISL1-expressing progenitors give rise to striatal neurons belonging to the striatonigral pathway
	is required for the normal development of striatonigral neurons
	marks the progenitors of the striatonigral pathway and is required for their development and survival

CELLULAR PROCESS

nucleotide, transcription

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component	LIM complex composed of ISL1 and LHX3 directs the specification of spinal motor neurons (MNs) in embryos
	ISL1-GATA3 transcription regulatory axis is essential for normal pyloric development
	crucial regulatory axis for the ventral axonal trajectory of developing spinal MNs, consisting of the ISL1-LHX3 complex, STAM1 and CXCR4

INTERACTION

DNA	binding to the enhancer region of the insulin gene

RNA

small molecule

protein	interacting with NEUROD1 (could activate insulin gene transcription synergistically)
	transcriptional activator for insulin gene expression, and the interactions of ISL1 with NEUROD1 are required for the transcriptional activity of the insulin gene
	FBXO25 acts as an ubiquitin E3 ligase to target cardiac transcription factors including NKX2-5, ISL1, and HAND1, indicating that cardiac protein homeostasis through FBXO25 has a pivotal impact on cardiac development
	binds to a known POU4F1-regulated enhancer in the NEUROD4 gene, suggesting a mechanism of interaction between these genes
	novel transcriptional regulator of LHX3
	ISL1 directly regulates FGF10 transcription during human cardiac outflow formation
	AJUBA binds ISL1, represses its transcriptional activity, and is also required for autorepression of ISL1 expression in an Retinoic acid (RA)-dependent manner
	LDB1 is a critical transcriptional coregulator during islet alpha-, beta-, and delta-cell development through ISL1-dependent and potentially ISL1-independent control
	CDH6 is necessary for the generation of ISL1-positive dorsal interneurons, as well as the initiation of pre-migratory neural crest cell emigration
	potent BARX1 functions in intestinal rotation and stomach myogenesis occur through ISL1, PITX1, SIX2 and PITX2, intermediary transcription factors
	LDB1 binds to the key regulator of cardiac progenitors, ISL1, and protects it from degradation
	is a transcription factor important for pancreatic islet cell development, maturation, and function, which largely requires interaction with LDB1 coregulator
	SSBP3 interacts with LDB1 and ISL1 in beta-cell lines and in human islets and is coexpressed with LDB1 and ISL1 pancreas tissue
	SSBP3 is a critical component of LDB1-ISL1 regulatory complexes, required for expression of critical beta-cell target genes
	NRDC controls beta-cell function via regulation of the ISL1-MAFA pathway

cell & other

REGULATION

Other

regulated by CTNNB1 in cardiovascular progenitors (required for multiple aspects of cardiogenesis)

ASSOCIATED DISORDERS

corresponding disease(s)

Susceptibility

to obesity to non insulin dependent diabetes mellitus, familial to non-syndromic congenital heart disease

Variant & Polymorphism SNP , other	SNP47A>G increases the body weight in diabetic morbidly obese
	genetic variation in ISL1 is associated with risk of non-syndromic congenital heart disease.

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS

Mice with a homozygous null mutation in the Isl1 gene exhibited growth retardation and heart abnormalities (Cai et al, 2003)

Mouse conditional knockout for Isl1 gene showed a loss of the nociceptive markers TrkA, TrkB and Runx1 and a near absence of cutaneous innervation, an excess of cell apoptosis, a ganglion size markedly diminished, a profound loss of cutaneous innervation. Mouse Isl1 CKO exhibits rofound deficits in the sensory innervation of the CNS and periphery, extensive changes in sensory gene expression, and markedly increased sensory apoptosis, with relative sparing of proprioceptor neuron (Sun et al, 2008)