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FLASH GENE

Symbol

BDNF

contributors: mct/pgu/shn - updated : 14-07-2016

HGNC name	brain-derived neurotrophic factor
HGNC id	1033

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	WAGR WAGR complex
Location	11p14.1      Physical location : 27.676.443 - 27.743.605
Synonym name	neurotrophin
	abrineurin
Synonym symbol(s)	NTF2, MGC34632, ANON2, BULN2

DNA

TYPE	functioning gene
STRUCTURE	67.16 kb     2 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
	Binding site   transcription factor   HRE
text structure	nine functional promoters that are used tissue and brain-region specifically
	promoters I, II, III, and IV (BDNF-PI, -PII, -PIII, and -PIV), BDNF-PI was markedly activated, as well as BDNF-PIII, by Ca(2+) signals evoked via neuronal activity
	BDNF-RE-1 is located around 100 bp upstream of BDNF exon II
	cis-elements and transcription factors regulating neuronal activity-dependent transcription of BDNF gene

MAPPING

cloned

Y

linked

N

status

confirmed

Map	pter - D11S1750 - D11S4152 - BDNF - D11S1324 - D11S4201 - cen
Authors	USCSC (2009)

RNA

TRANSCRIPTS	type	messenger

text	variants 1, 2, 4, 5, and 7-16 encode the same isoform (a)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_170735 1 - 4755 NP_733931 - 247 - 1991 1889807 also called variant 1/isoform a or IX the longest transcript NM_170732 2 - 4125 NP_733928 - 247 - 1991 1889807 also called variant 2/isoform a or IIc, BDNF2C, or 2-5 an additional segment in the 5'UTR NM_170731 2 - 4338 NP_733927 - 255 - 1991 1889807 also called variant 3/isoform b or I, BDNF1, or 1-5 an additional segment in the 5'UTR and in the coding region NM_001709 2 - 4016 NP_001700 - 247 - 1991 1889807 also called variant 4/isoform a or VIb or BDNF5 an additional segment in the 5'UTR NM_170733 2 - 4028 NP_733929 - 247 - 1991 1889807 also called variant 5/isoform a or IV, BDNF4, or 3-5 an additional segment in the 5'UTR NM_170734 2 - 3976 NP_733930 - 262 - 1991 1889807 also called variant 6/isoform c or VIIb, BDNF6B, or 4I-5 an additional segment in the 5'UTR and in the coding region NM_001143805 2 - 3827 NP_001137277 - 247 - 1991 1889807 also called variant 7/isoform a or IIa or BDNF2A NM_001143806 2 - 4042 NP_001137278 - 247 - 1991 1889807 also called variant 8/isoform a or BDNF2B NM_001143807 2 - 3928 NP_001137279 - 247 - 1991 1889807 also called variant 9/isoform a or BDNF3 NM_001143808 2 - 3764 NP_001137280 - 247 - 1991 1889807 also called variant 10/isoform a or Va NM_001143809 2 - 3774 NP_001137281 - 276 - 1991 1889807 also called variant 17/isoform d or Vb NM_001143810 3 - 4057 NP_001137282 - 329 - 1991 1889807 also called variant 18/isoform e or V-VIII NM_001143811 4 - 4174 NP_001137283 - 247 - 1991 1889807 also called variant 11/isoform a or V-VIII-VIIIh NM_001143812 2 - 3916 NP_001137284 - 247 - 1991 1889807 aso called variant 12/isoform a or Vh NM_001143813 2 - 3998 NP_001137285 - 247 - 1991 1889807 also called variant 13/isoform a or VIa NM_001143814 3 - 4123 NP_001137286 - 247 - 1991 1889807 also called variant 14/isoform a or VIb-IXbd NM_001143815 2 - 3875 NP_001137287 - 247 - 1991 1889807 also called variant 15/isoform a NM_001143816 2 - 4521 NP_001137288 - 247 - 1991 1889807 also called variant 16/isoform a or IXabd

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 Nervous brain basal nuclei     highly Homo sapiens Adult   brain limbic system hippocampus     Homo sapiens Adult   brain limbic system hippocampus   highly Homo sapiens Adult   brain forebrain cerebral cortex   highly Homo sapiens Adult   brain hindbrain medulla oblongata   highly Homo sapiens Adult   brain hindbrain cerebellum   highly Homo sapiens Adult Reproductive female system placenta     moderately Homo sapiens Adult

cells

System Cell Pubmed Species Stage Rna symbol Nervous neuron Homo sapiens Adult Nervous Schawnn cell Homo sapiens Adult

cell lineage
cell lines
fluid/secretion	in human milk

at STAGE

physiological period

embryo

Text	anterior segment of the developing eye

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains

isoforms

Precursor

synthesized as a precursor (pro-BDNF) (PMID: 19996106)

HOMOLOGY

interspecies	ortholog to Bdnf, Mus musculus
	ortholog to Bdnf, Rattus norvegicus
	ortholog to bdnf, Danio rerio
	ortholog to BDNF, Pan troglodytes

Homologene

FAMILY

NGF beta family

CATEGORY

transcription factor , signaling growth factor

SUBCELLULAR LOCALIZATION	extracellular
	intracellular
	intracellular,cytoplasm

basic FUNCTION	promoting the survival of neuronal cells located in the central nervous system or directly connected to it
	supporting populations of sensory neurons via NRTK2 or NRTK3 signaling
	involved in memory and hippocampal function
	may be playing a role in the regulation and modulation of oocyte maturation
	is a crucial signaling molecule between microglia and neurons
	promoting the activation of CFL1 by reducing the phosphorylation of CFL1
	promotes the maturation of cortical inhibition during early postnatal life, thereby regulating the critical period for visual cortical plasticity
	critical for the normal development and function of central 5-HT neurons and for the elaboration of behaviors that depend on these nerve cells
	responsible for inducing normal expression of the dopamine D3 receptor in nucleus accumbens both during development and in adulthood
	an essential role for BDNF in mediating long-term neural and behavioral plasticity in response to aversive social experiences
	involved in neurite outgrowth, early neuronal cell development, neuropeptide signaling/synthesis and neuronal receptor
	regulating retinal growth cone filopodial dynamics through actin depolymerizing factor/cofilin CFL1
	playing a role in energy homeostasis, as well as in cognitive function, memory, and behavior
	plays a pivotal role in brain development and synaptic plasticity
	with BDNF, are essential in promoting normal development of the central nervous system )
	BDNF and NTRK2 play important roles in controlling respiration, movement, balance and feeding in the brainstem and that the NTRK2 is the most age-sensitive component of this system, especially in the hippocampus
	important mediator of activity-dependent functions of the nervous system and its expression is dysregulated in several neuropsychiatric disorders
	BDNF/TrkB signaling promotes neuronal survival and can help neurons resist toxic insults
	secreted neurotrophin essential for the survival and differentiation of many neuronal populations, that serves as a self-amplifying autocrine factor in promoting axon formation in embryonic hippocampal neurons by triggering two nested positive-feedback mechanisms
	protects endothelial progenitor cells by increasing expression of SOD2 thereby enhancing their antioxidant capacity
	NR4A2 and BDNF show a similar expression pattern during postnatal cerebellar development
	cooperative roles of BDNF expression in neurons and Schwann cells are modulated by exercise to facilitate nerve regeneration
	seems to be involved in regulation of synaptic plasticity and neurogenesis
	expression of NTRK2 and BDNF is associated with poor prognosis in non-small cell lung cancer patients
	is a key positive regulator of neural plasticity, promoting, for example, the actions of stimulant drugs of abuse such as cocaine, and is a negative modulator of morphine action
	is necessary for ciliary localization of NTRK2 receptor and activation by BDNF
	in the cochlar nucleus, NTF3 had a strong impact on enhancement of neuronal survival, whereas BDNF stimulated neuronal survival and axonal outgrowth
	NTF3 and BDNF are critical for sensory neuron survival and establishment of neuronal projections to sensory epithelia in the embryonic inner ear

CELLULAR PROCESS

nucleotide, transcription

PHYSIOLOGICAL PROCESS

text	neuron proliferation, differentiation and survival through its upstake at nerve terminals and retrograde transport to the cell body, also transported anterogradely, released on neuron depolarization

PATHWAY

metabolism

signaling

signal transduction

	triggering rapid intracellular signals and action potentials in central neurons
	BDNF/NTRK2 signaling activates PI3-kinase that promotes anterograde transport of NTRK2 in the putative axon, further enhancing local BDNF/NTRK2 signaling
	EEF2K/EEF2 pathway is a key biochemical sensor that couple neuronal activity to spine plasticity, by controlling the dendritic translation of BDNF
	signaling axis between BDNF and NFATC4 in adult hippocampal neural progenitor cells

a component	component of a heterodimer with NTF3
	BDNF/NTRK2 signaling is essential for the development of photoreceptors and for synaptic communication between photoreceptors and second order retinal neurons

INTERACTION

DNA

RNA

small molecule

protein	neurotrophin-3, NT-3 and nerve growth factor, NGF
	TRKB
	nitric oxide synthase, NOS
	PSA-NCAM
	ERalpha
	CAPS2
	Sortilin
	REST-target gene
	uses CREB1 and EGR3 to regulate NMDA receptor levels in cortical neurons
	nuclear GNB2L1 is required to promote the transcription of the brain-derived neurotrophic factor (BDNF) 7)
	PARD3 regulates RAC1 activation by BDNF but not by NRG1-Type III in Schwann cells, although both ligands activate RAC1
	COMT on human cortical plasticity
	progesterone-induced BDNF release was dependent on the expression of PGRMC1
	SIK1 mediates the activation of MEF2-dependent transcription by BDNF
	together with other epigenetic mechanisms, AICDA plays a key role in regulating activity-dependent BDNF expression in post-mitotic cortical neurons
	BDNF induces the release of CYFIP1 from EIF4E, and this depends on MNKNK1
	direct effect of ELAVL4 on regulating translation of dendritic BDNF mRNAs to mediate local and activity-dependent increases in dendritic BDNF synthesis
	protective effects of BDNF against CRP-induced inflammation in women
	BDNF, via truncated NTRK2, modulates SLC6A9 and SLC6A5 in astrocytes
	LRIG1 physically interacts with NTRK2 and attenuates BDNF signaling
	BDNF rescues ACTL6B-dependent synaptic plasticity and cocaine-associated memory in the nucleus accumbens

cell & other

REGULATION

induced by

cortical neurons

ASSOCIATED DISORDERS

corresponding disease(s)

WAGR

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --low   low RNA and protein levels in brain of Alzheimer and Huntington disease patients constitutional     --low   reduced expression of brain-derived neurotrophic factor in the cerebrospinal fluid samples of infants with Ondine's curse constitutional     --low   in patients with major depressive disorder constitutional     --over   during migraine attacks, and in cluster headache, further supporting the involvement of BDNF in the pathophysiology of these primary headaches constitutional     --low   in the caudal nucleus of the solitary tract in the sudden infant death syndrome constitutional     --low   significant decrease in BDNF expression and impairment of downstream signaling in the aged hippocampus

Susceptibility

to bipolar disorder and depression to obsessive -compulsive disorder to aberrant eating behaviors (anorexia and bulimia ) to obesity in WAGR to Parkinson disease to psychosis to schizophrenia to obesity

Variant & Polymorphism SNP	Val66Met is associated with alterations in brain anatomy and memory, and play a key role in genetic predispositions to anxiety and depressive disorders
	VAL66MET increasing the risk of Parkinson disease and psychosis
	associated to obesity risk

Candidate gene	blood BDNF levels could be used as a biomarker to validate drugs aimed at restoring the defective intracellular vesicular dynamics in HD (Huntington disease)
Marker	mature BDNF may serve as a biomarker for major depressive disorder
Therapy target	delivery of BDNF reverses the deficit in memory persistence caused by inhibition of hippocampal protein synthesis
	System Type Disorder Pubmed neurology     manipulation of BDNF/TrkB signaling might have therapeutic efficacy in motor neuron diseases neurology neurodegenerative alzheimer neuroprotective effects of entorhinal BDNF administration in animal models of Alzheimer's disease, with extension of therapeutic benefits into the degenerating hippocampus neurology neurodegenerative alzheimer a potential therapy for Alzheimer's disease miscelleaneous senescence   , epigenetic or pharmacological enhancement of BDNF-NTRK2 signaling could be a promising strategy for reversing cognitive aging

ANIMAL & CELL MODELS

	maturation of GABAergic innervation and inhibition was accelerated in mice in which the postnatal rise of brain-derived neurotrophic factor (BDNF) was accelerated and they showed a precocious development of visual acuity and an earlier termination of the critical period for ocular dominance plasticity
	early postnatal lethality of BDNF null mice
	heterozygous BDNF(+/-) mice develop enhanced intermale aggressiveness and hyperphagia accompanied by significant weight gain in early adulthood
	transgenic overexpression of BDNF in mouse has a facilitatory effect on anxiety-like behavior, concomitant with increased spinogenesis in the basolateral amygdala and antidepressant effects
	BDNF(Val66Met/Val66Met) mice exhibited increased anxiety-related behaviors in stressful settings