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FLASH GENE

Symbol

DLK1

contributors: mct - updated : 06-01-2016

HGNC name	delta-like 1 homolog (Drosophila)
HGNC id	2907

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	19.17 kb     5 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

provisional

regionally located

in DLK1-MEG3 (GTL2) reciprocally imprinted region

RNA

TRANSCRIPTS	type	messenger

text	? other transcripts

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_003836 5 splicing 1599 NP_003827 41.1 383 - 1995 7711066 variant 5 - splicing 1337 isoform 5 - 310 - 2006 16403460 also called Pref1 Secredeltin with 219bp del epidermal growth factor-like domain 6 and parts of the juxtamembrane region variant 4 - splicing 1550 isoform 4 - 286 - 1995 7711066 also called pG2 variant 2 - - - isoform 2 - 204 - 2006 16403460 also called variant brevideltin stop codon due to a frame-shift, leading to truncated protein variant 3 - - - isoform 3 - 213 - 2006 16403460 also called variant brevideltinin stop codon due to a frame-shift, leading to truncated protein

EXPRESSION

Type

widely

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 Cardiovascular heart       highly Endocrine adrenal gland cortex     highly   neuroendocrine pituitary     highly   pancreas         Reproductive female system ovary     highly   female system placenta     highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum skeletal

cell lineage	nascent hair cells of inner ear, highly in preadipocytes
cell lines	tumor with neuroendocrine features
fluid/secretion

at STAGE

physiological period

embryo, pregnancy

Text	placenta, and widely during embryonic development

IMPRINTING

paternally

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	six EGF-like extracellular repeats
	a unique transmembrane segment
	a short intracellular region
	N and O glycosylation sites

conjugated

GlycoP

mono polymer

monomer

HOMOLOGY

interspecies	homolog to delta Drosophila-like 1
	homolog to Drosophila Notch
	homolog to murine Dlk (86.2pc)
	homolog to C.elegans mo2g9.2
	homolog to rattus Dlk (85.4pc)

intraspecies	homolog to DLL4
	homolog to DLK2

Homologene

FAMILY

EGF-like homeotic family

CATEGORY

regulatory , antigen , tumor suppressor

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,cytosolic,vesicle
text	secretory vesicles, type I transmembrane protein
	membrane-bound precursor that is subsequently cleaved to generate the circulating form
	secretory granules of the beta cells within the islets of Langherans

basic FUNCTION	NOTCH1 ligand involved in cell differentiation in a justacrine/paracrine manner and in the pathogenesis of NF1
	participating in the control of cell differentiation of several cell type, including small cell lung cancer lines, immune stem cells, B cells and adrenal glomerulose cells
	activates the MEK/ERK pathway to inhibit adipocyte differentiation
	may play a role in the formation or progression of gliomas
	coordinated expression of DLK1 and DLK2 may modulate adipogenesis
	have ability to inhibit preadipocyte differentiation, and to regulate the differentiation of several other cell types through unknown mechanisms
	by inducing Sox9, promotes chondrogenic induction of mesenchymal cells but inhibits differentiation into adipocytes
	activating the MAPK kinase/ERK pathway
	enhancing cancer cell stemness and tumorigenicity
	dispensable during embryonic neurogenesis
	DLK1 secreted by SVZ (subventricular zone) niche astrocytes regulates in neural stem cells self-renewal, probably in combination with other niche factors
	neurogenic continuum, initiating at the early postnatal period and being maintained over the lifetime
	inhibitory role for DLK1 in the regulation of angiogenesis, mediated by antagonism of the NOTCH pathway,
	role for DLK1 in the post-natal development of hypothalamic functions, most notably those regulated by the arginine-vasopressin and oxytocin systems
	major dual inhibitory function of DLK1 on adipogenesis, which places DLK1 as a master regulator of preadipocyte homeostasis
	its expression is not essential for the normal development of beta-cells, somatotrophs and endothelial cells
	imprinted gene best known for its ability to inhibit adipogenesis, is a crucial regulator of the myogenic program in skeletal muscle
	dual biological function of DLK1 as an enhancer of muscle development, but as an inhibitor of adult muscle regeneration

CELLULAR PROCESS	cell life, differentiation

PHYSIOLOGICAL PROCESS

development

text	neuroendocrine differentiation, inner ear development

PATHWAY

metabolism

signaling

a component

INTERACTION

DNA

RNA

small molecule

protein	binding NOTCH
	interacting with GH (regulates GH expression and GH is a DLK1-regulated target gene)
	novel regulatory mechanism for FGF18 signaling involving GLG1 and DLK1
	fibronectin FN1) is a DLK1 interacting protein (the inhibitory role of DLK1 is, at least in part, through DLK1 binding to the C-terminal region of fibronectin, which, in turn, activates integrin signaling to result in MEK/ERK activation and the inhibition of adipocyte differentiation)
	SORT1 binds to DLK1, an inhibitor of adipocyte differentiation, and the overexpression of SORT1 prevents DLK1 downregulation, leading to enhanced inhibition of adipogenesis
	DLK1 genes may play an important role in the GSK3B-mediated osteoblast apoptosis process

cell & other

REGULATION

ASSOCIATED DISORDERS

corresponding disease(s)

UPD14M , UPD14P , DEL14Q32

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --low   in renal cell carcinoma by gain of methylation upstream of the untranslated MEG3 leading to pathological downregulation tumoral     --over   in GH-secreting (GH-S) pituitary tumors, and in gliomas tumoral     --over   in hepatocellular carcinoma, through deregulation of genomic DNA methylation of the imprinted domain

Susceptibility

to type 1 diabetes

Variant & Polymorphism

Candidate gene	associated with child and adolescent obesity
Marker
Therapy target

ANIMAL & CELL MODELS

	transgenic mice overexpressing soluble DLK1 in adipose tissue or liver show a marked decrease in adiposity, with reduced adipogenesis and adipocyte marker expression
	Dlk1(-/-) mice were developmentally retarded in their muscle mass and function owing to inhibition of the myogenic program during embryogenesis