EMX1

Summary

EMX1 (empty spiracles homeobox 1, HGNC:3340) is a protein-coding gene on chromosome 2p13.2, encoding Homeobox protein EMX1 (Q04741). Transcription factor, which in cooperation with EMX2, acts to generate the boundary between the roof and archipallium in the developing brain.

Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in brain development; neuron differentiation; and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including nervous system development; neuroepithelial cell differentiation; and regulation of oligodendrocyte progenitor proliferation. Located in chromosome and nucleolus.

Source: NCBI Gene 2016 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 41 total — 1 pathogenic
• MANE Select transcript: NM_004097

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3340
Approved symbol	EMX1
Name	empty spiracles homeobox 1
Location	2p13.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000135638
Ensembl biotype	protein_coding
OMIM	600034
Entrez	2016

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000258106, ENST00000394111, ENST00000464675, ENST00000473732, ENST00000491023, ENST00000616281, ENST00000967897

RefSeq mRNA: 1 — MANE Select: NM_004097 NM_004097

CCDS: CCDS1921

Canonical transcript exons

ENST00000258106 — 3 exons

Exon	Start	End
ENSE00000846613	72917519	72918372
ENSE00002324819	72933787	72934891
ENSE00003583246	72924309	72924493

Expression profiles

Bgee: expression breadth ubiquitous, 116 present calls, max score 95.86.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.6168 / max 60.1254, expressed in 179 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
20934	0.3447	140
20936	0.1281	63
20937	0.0548	31
20935	0.0339	14
20933	0.0305	10
20938	0.0248	9

Top tissues by expression

258 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	95.86	gold quality
cortical plate	UBERON:0005343	93.79	gold quality
ventricular zone	UBERON:0003053	92.95	gold quality
oocyte	CL:0000023	90.78	gold quality
metanephros cortex	UBERON:0010533	89.53	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.65	gold quality
right frontal lobe	UBERON:0002810	87.38	gold quality
adult mammalian kidney	UBERON:0000082	86.68	gold quality
Brodmann (1909) area 9	UBERON:0013540	85.37	gold quality
prefrontal cortex	UBERON:0000451	85.22	gold quality
cingulate cortex	UBERON:0003027	84.17	gold quality
anterior cingulate cortex	UBERON:0009835	84.00	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	83.89	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.23	gold quality
secondary oocyte	CL:0000655	82.56	gold quality
neocortex	UBERON:0001950	81.44	gold quality
frontal cortex	UBERON:0001870	80.62	gold quality
cerebral cortex	UBERON:0000956	78.62	gold quality
embryo	UBERON:0000922	77.84	gold quality
kidney	UBERON:0002113	77.38	gold quality
amygdala	UBERON:0001876	76.02	gold quality
primary visual cortex	UBERON:0002436	75.53	gold quality
cortex of kidney	UBERON:0001225	74.01	gold quality
Ammon’s horn	UBERON:0001954	71.82	gold quality
mucosa of transverse colon	UBERON:0004991	69.22	gold quality
left testis	UBERON:0004533	69.01	gold quality
right testis	UBERON:0004534	68.98	gold quality
occipital lobe	UBERON:0002021	68.48	gold quality
temporal lobe	UBERON:0001871	68.44	gold quality
renal medulla	UBERON:0000362	68.02	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	42.53
E-HCAD-5	yes	33.63
E-ANND-3	no	1.29

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
APC
NRP1	Activation

JASPAR motifs

Motif	Name	Family
MA0612.1	EMX1	NK
MA0612.2	EMX1	NK
MA0612.3	EMX1	NK

JASPAR matrix evidence (PMIDs): PMID:23332764, PMID:25215497

Upstream regulators (CollecTRI, top): SIX3

miRNA regulators (miRDB)

34 targeting EMX1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-6892-3P	99.68	66.40	1178
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-18A-3P	99.56	65.68	1092
HSA-MIR-642A-5P	99.51	65.10	1152
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-3190-5P	98.87	64.89	1345
HSA-MIR-7851-3P	98.72	64.88	980
HSA-MIR-3938	98.72	66.07	834
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-4646-3P	98.65	66.98	693
HSA-MIR-4700-5P	98.63	67.43	1915
HSA-MIR-9500	98.62	66.54	1845
HSA-MIR-6780A-3P	98.42	67.49	1518
HSA-MIR-3155A	98.16	66.09	965
HSA-MIR-3155B	98.16	66.09	965
HSA-MIR-484	98.16	66.92	1074
HSA-MIR-8089	97.74	66.21	1698
HSA-MIR-4667-5P	97.61	66.67	1683
HSA-MIR-6779-3P	97.51	65.82	789
HSA-MIR-3116	97.07	65.78	1324
HSA-MIR-6773-5P	97.04	64.30	595
HSA-MIR-6724-5P	96.41	63.11	507
HSA-MIR-1291	96.28	65.89	1224

Literature-anchored findings (GeneRIF, showing 5)

• An intersectional fate-mapping analysis reveals that transgenic Emx1-lineage cells coexpressing Dlx exclusively generate medium spiny neurons but do not contribute to the excitatory neurons in the amygdala. (PMID:20016109)
• Regulation of sarcomagenesis by the empty spiracles homeobox genes EMX1 and EMX2. (PMID:34016958)
• Empty spiracles homeobox genes EMX1 and EMX2 regulate WNT pathway activation in sarcomagenesis. (PMID:34364391)
• EMX1 functions as a tumor inhibitor in spinal cord glioma through transcriptional suppression of WASF2 and inactivation of the Wnt/beta-catenin axis. (PMID:35849030)
• Generation of human excitatory forebrain neurons by cooperative binding of proneural NGN2 and homeobox factor EMX1. (PMID:38446849)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	emx1	ENSDARG00000039569
mus_musculus	Emx1	ENSMUSG00000033726
rattus_norvegicus	Emx1	ENSRNOG00000015493

Paralogs (3): VAX2 (ENSG00000116035), VAX1 (ENSG00000148704), EMX2 (ENSG00000170370)

Protein

Protein identifiers

Homeobox protein EMX1 — Q04741 (reviewed: Q04741)

Alternative names: Empty spiracles homolog 1, Empty spiracles-like protein 1

All UniProt accessions (3): A0A087WZF2, Q04741, F8W1B5

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor, which in cooperation with EMX2, acts to generate the boundary between the roof and archipallium in the developing brain. May function in combinations with OTX1/2 to specify cell fates in the developing central nervous system.

Subunit / interactions. Interacts with WRD11 (via the N-terminal and the central portion of the protein); the interaction associates EMX1 with GLI3.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Cerebral cortex.

Similarity. Belongs to the EMX homeobox family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q04741-1	1	yes
Q04741-2	2

RefSeq proteins (1): NP_004088* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR020479	HD_metazoa	Domain
IPR050877	EMX-VAX-Noto_Homeobox_TFs	Family

Pfam: PF00046

UniProt features (6 total): splice variant 2, chain 1, DNA-binding region 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q04741-F1	64.07	0.20

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 104 (showing top): RNGTGGGC_UNKNOWN, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, MYOGENIN_Q6, GOBP_NEURON_PROJECTION_EXTENSION, GCANCTGNY_MYOD_Q6, GOBP_GROWTH, GOBP_NEUROGENESIS, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_FOREBRAIN_REGIONALIZATION, GOBP_FOREBRAIN_GENERATION_OF_NEURONS, GOBP_NEURAL_PRECURSOR_CELL_PROLIFERATION, GOBP_CEREBRAL_CORTEX_NEURON_DIFFERENTIATION, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT

GO Biological Process (18): in utero embryonic development (GO:0001701), regulation of transcription by RNA polymerase II (GO:0006357), central nervous system development (GO:0007417), brain development (GO:0007420), response to xenobiotic stimulus (GO:0009410), post-embryonic development (GO:0009791), cerebral cortex regionalization (GO:0021796), cerebral cortex neuron differentiation (GO:0021895), neuron differentiation (GO:0030182), brain morphogenesis (GO:0048854), homeostasis of number of cells (GO:0048872), radial glial cell differentiation (GO:0060019), neuroepithelial cell differentiation (GO:0060563), regulation of oligodendrocyte progenitor proliferation (GO:0070445), neuron projection extension (GO:1990138), regulation of DNA-templated transcription (GO:0006355), telencephalon development (GO:0021537), cerebral cortex development (GO:0021987)

GO Molecular Function (5): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), chromosome (GO:0005694), nucleolus (GO:0005730), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure development	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
cellular anatomical structure	2
intracellular membraneless organelle	2
chordate embryonic development	1
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
nervous system development	1
system development	1
central nervous system development	1
animal organ development	1
head development	1
response to chemical	1
multicellular organism development	1
multicellular organismal process	1
regionalization	1
telencephalon regionalization	1
cerebral cortex development	1
forebrain neuron differentiation	1
cell differentiation	1
generation of neurons	1
brain development	1
animal organ morphogenesis	1
multicellular organismal-level homeostasis	1
glial cell differentiation	1
columnar/cuboidal epithelial cell differentiation	1
oligodendrocyte progenitor proliferation	1
regulation of neural precursor cell proliferation	1
developmental cell growth	1
neuron projection morphogenesis	1
developmental growth involved in morphogenesis	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
forebrain development	1
pallium development	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1

Protein interactions and networks

STRING

1448 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EMX1	TBR1	Q16650	804
EMX1	FOXG1	P55315	785
EMX1	NEUROD6	Q96NK8	714
EMX1	SHH	Q15465	668
EMX1	FGF8	P55075	631
EMX1	BCL11B	Q9C0K0	631
EMX1	NES	P48681	626
EMX1	SATB2	Q9UPW6	624
EMX1	EOMES	O95936	621
EMX1	FANCF	Q9NPI8	619
EMX1	CUX1	P39880	615
EMX1	NEUROG2	Q9H2A3	613
EMX1	PVALB	P20472	608
EMX1	FEZF2	Q8TBJ5	601
EMX1	CAMK2A	Q9UQM7	587

IntAct

13 interactions, top by confidence:

A	B	Type	Score
WDR11	EMX1	psi-mi:“MI:0915”(physical association)	0.500
GLI3	EMX1	psi-mi:“MI:0915”(physical association)	0.500
GLI3	EMX1	psi-mi:“MI:0914”(association)	0.500
EMX1	GTF2A1L	psi-mi:“MI:0915”(physical association)	0.370
EMX1	PRDM4	psi-mi:“MI:0915”(physical association)	0.370
ELK1	EMX1	psi-mi:“MI:0915”(physical association)	0.370
EMX1	HOXA10	psi-mi:“MI:0915”(physical association)	0.370
EMX1	POLR2D	psi-mi:“MI:0915”(physical association)	0.370
EMX1	ALX4	psi-mi:“MI:0915”(physical association)	0.370
EMX1	TP63	psi-mi:“MI:0915”(physical association)	0.370
WDR11	GLI3	psi-mi:“MI:0914”(association)	0.350

BioGRID (9): EMX1 (Protein-RNA), HSPH1 (Cross-Linking-MS (XL-MS)), EMX1 (Two-hybrid), HOXA10 (Two-hybrid), POLR2D (Two-hybrid), TP63 (Two-hybrid), GTF2A1L (Two-hybrid), PRDM4 (Two-hybrid), ALX4 (Two-hybrid)

ESM2 similar proteins: A0JPN1, A1YEY5, A1YF16, A1YFI3, A1YG57, A1YG93, A2T733, A2T764, A2T7P4, A6NJ46, A7MB54, O02786, O42230, O43711, O43763, O55144, O57601, O93367, O95096, P09633, P31274, P35548, P42586, P43120, P43345, P43697, P48031, P50223, P52946, P52947, P52951, P53545, P56915, P63156, P63157, Q02591, Q03014, Q03358, Q04741, Q04742

Diamond homologs: A2RU54, A5YC49, A6NHT5, A6NJ46, A8XJD0, D2KQB0, O08686, O35762, O42230, O43711, O43763, O55144, O57601, O70218, O88181, O93366, O93367, O93590, P02830, P15858, P19601, P20269, P22544, P22807, P22809, P28468, P31314, P40764, P42580, P42581, P43345, P43687, P48031, P52950, P53547, P53772, P53775, P56407, P63156, P63157

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
EMX1	“up-regulates quantity by expression”	NRP1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

41 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	40
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
60181	GRCh38/hg38 2p13.2(chr2:72861062-72992130)x1	Pathogenic

SpliceAI

607 predictions. Top by Δscore:

Variant	Effect	Δscore
2:72924267:T:TA	acceptor_gain	1.0000
2:72924271:T:TA	acceptor_gain	1.0000
2:72924274:A:AG	acceptor_gain	1.0000
2:72924274:ACCT:A	acceptor_gain	1.0000
2:72924275:C:G	acceptor_gain	1.0000
2:72924277:T:TA	acceptor_gain	1.0000
2:72924279:C:CA	acceptor_gain	1.0000
2:72924491:CAGGT:C	donor_loss	1.0000
2:72924492:AGG:A	donor_loss	1.0000
2:72924493:GGT:G	donor_loss	1.0000
2:72924494:GT:G	donor_loss	1.0000
2:72924495:T:G	donor_loss	1.0000
2:72933779:T:A	acceptor_gain	1.0000
2:72918371:GG:G	donor_gain	0.9900
2:72918372:GG:G	donor_gain	0.9900
2:72924281:T:TA	acceptor_gain	0.9900
2:72924283:T:TA	acceptor_gain	0.9900
2:72924286:T:A	acceptor_gain	0.9900
2:72924289:C:A	acceptor_gain	0.9900
2:72924292:C:CA	acceptor_gain	0.9900
2:72924295:C:CA	acceptor_gain	0.9900
2:72924490:GCAG:G	donor_gain	0.9900
2:72933783:CCAG:C	acceptor_loss	0.9900
2:72933784:CAGGT:C	acceptor_loss	0.9900
2:72933785:A:G	acceptor_loss	0.9900
2:72933786:G:GT	acceptor_loss	0.9900
2:72924298:C:CA	acceptor_gain	0.9800
2:72924494:G:GG	donor_gain	0.9800
2:72933780:G:A	acceptor_gain	0.9800
2:72933785:A:AG	acceptor_gain	0.9800

AlphaMissense

1862 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000459269 (2:72917019 G>A), RS1000488950 (2:72917279 C>G,T), RS1000605674 (2:72922795 C>T), RS1000792836 (2:72918981 G>A), RS1000805139 (2:72929268 C>G), RS1000948490 (2:72925118 T>C), RS1001002678 (2:72914903 G>T), RS1001038049 (2:72915303 G>A,C), RS1001240730 (2:72934613 C>A,T), RS1001521130 (2:72916056 T>C), RS1001594889 (2:72930365 G>A), RS1001599260 (2:72921262 G>A,T), RS1001672492 (2:72918555 G>T), RS1001744991 (2:72920965 T>C), RS1001777544 (2:72924231 C>T)

Disease associations

OMIM: gene MIM:600034 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST004946_91	Schizophrenia	2.000000e-10
GCST007201_21	Schizophrenia	1.000000e-08
GCST010725_60	Malaria	7.000000e-06
GCST010725_79	Malaria	5.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	increases expression, affects response to substance	1
CGP 52608	increases reaction, affects binding	1
pyrachlostrobin	decreases expression	1
bisphenol S	decreases methylation	1
jinfukang	affects cotreatment, increases expression	1
picoxystrobin	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Acetaminophen	decreases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation	1
Cisplatin	affects cotreatment, increases expression	1
Copper	decreases expression, affects cotreatment	1
Lipopolysaccharides	affects response to substance, increases expression	1
Rotenone	decreases expression	1
Smoke	increases expression	1
Testosterone	increases expression	1
Triclosan	increases expression	1
Urethane	decreases expression	1
Aflatoxin B1	decreases methylation	1
Asbestos, Crocidolite	decreases methylation	1
Asbestos, Amosite	decreases methylation	1
Okadaic Acid	decreases expression	1
Acrylamide	decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.