BHE22_MOUSE
ID BHE22_MOUSE Reviewed; 355 AA.
AC Q8C6A8; Q9JL05;
DT 06-FEB-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 124.
DE RecName: Full=Class E basic helix-loop-helix protein 22;
DE Short=bHLHe22;
DE AltName: Full=Class B basic helix-loop-helix protein 5;
DE Short=bHLHb5;
DE AltName: Full=Protein BETA3;
GN Name=Bhlhe22; Synonyms=Bhlhb5;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RX PubMed=12213201; DOI=10.1006/geno.2002.6833;
RA Xu Z.-P., Dutra A., Stellrecht C.M., Wu C., Piatigorsky J., Saunders G.F.;
RT "Functional and structural characterization of the human gene BHLHB5,
RT encoding a basic helix-loop-helix transcription factor.";
RL Genomics 80:311-318(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Head;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP DEVELOPMENTAL STAGE.
RX PubMed=14643684; DOI=10.1016/s1567-133x(03)00135-2;
RA Brunelli S., Innocenzi A., Cossu G.;
RT "Bhlhb5 is expressed in the CNS and sensory organs during mouse embryonic
RT development.";
RL Gene Expr. Patterns 3:755-759(2003).
RN [5]
RP FUNCTION, AND DEVELOPMENTAL STAGE.
RX PubMed=17092954; DOI=10.1242/dev.02664;
RA Feng L., Xie X., Joshi P.S., Yang Z., Shibasaki K., Chow R.L., Gan L.;
RT "Requirement for Bhlhb5 in the specification of amacrine and cone bipolar
RT subtypes in mouse retina.";
RL Development 133:4815-4825(2006).
RN [6]
RP FUNCTION, DEVELOPMENTAL STAGE, AND DISRUPTION PHENOTYPE.
RX PubMed=18957218; DOI=10.1016/j.neuron.2008.08.006;
RA Joshi P.S., Molyneaux B.J., Feng L., Xie X., Macklis J.D., Gan L.;
RT "Bhlhb5 regulates the postmitotic acquisition of area identities in layers
RT II-V of the developing neocortex.";
RL Neuron 60:258-272(2008).
RN [7]
RP FUNCTION, DEVELOPMENTAL STAGE, AND DISRUPTION PHENOTYPE.
RX PubMed=20346763; DOI=10.1016/j.neuron.2010.02.025;
RA Ross S.E., Mardinly A.R., McCord A.E., Zurawski J., Cohen S., Jung C.,
RA Hu L., Mok S.I., Shah A., Savner E.M., Tolias C., Corfas R., Chen S.,
RA Inquimbert P., Xu Y., McInnes R.R., Rice F.L., Corfas G., Ma Q.,
RA Woolf C.J., Greenberg M.E.;
RT "Loss of inhibitory interneurons in the dorsal spinal cord and elevated
RT itch in Bhlhb5 mutant mice.";
RL Neuron 65:886-898(2010).
RN [8]
RP FUNCTION, AND INTERACTION WITH PRDM8.
RX PubMed=22284184; DOI=10.1016/j.neuron.2011.09.035;
RA Ross S.E., McCord A.E., Jung C., Atan D., Mok S.I., Hemberg M., Kim T.K.,
RA Salogiannis J., Hu L., Cohen S., Lin Y., Harrar D., McInnes R.R.,
RA Greenberg M.E.;
RT "Bhlhb5 and Prdm8 form a repressor complex involved in neuronal circuit
RT assembly.";
RL Neuron 73:292-303(2012).
CC -!- FUNCTION: Inhibits DNA binding of TCF3/E47 homodimers and TCF3
CC (E47)/NEUROD1 heterodimers and acts as a strong repressor of Neurod1
CC and Myod-responsive genes, probably by heterodimerization with class a
CC basic helix-loop-helix factors. Despite the presence of an intact basic
CC domain, does not bind to DNA (By similarity). In the brain, may
CC function as an area-specific transcription factor that regulates the
CC postmitotic acquisition of area identities and elucidate the genetic
CC hierarchy between progenitors and postmitotic neurons driving
CC neocortical arealization. May be required for the survival of a
CC specific population of inhibitory neurons in the superficial laminae of
CC the spinal cord dorsal horn that may regulate pruritis. Seems to play a
CC crucial role in the retinogenesis, in the specification of amacrine and
CC bipolar subtypes. Forms with PRDM8 a transcriptional repressor complex
CC controlling genes involved in neural development and neuronal
CC differentiation (PubMed:22284184). {ECO:0000250,
CC ECO:0000269|PubMed:17092954, ECO:0000269|PubMed:18957218,
CC ECO:0000269|PubMed:20346763, ECO:0000269|PubMed:22284184}.
CC -!- SUBUNIT: Interacts with PRDM8. {ECO:0000269|PubMed:22284184}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000305}.
CC -!- TISSUE SPECIFICITY: Brain-specific, with the highest expression in the
CC cerebellum. {ECO:0000269|PubMed:12213201}.
CC -!- DEVELOPMENTAL STAGE: Expressed at 11.5 dpc within the neuroblast layer
CC (NBL) of the central retina. As retinogenesis progressed from central
CC to peripheral retina from 12 dpc to 15.5 dpc, expression expanded to
CC the entire retina with the majority of Bhlhb5+ cells being detected in
CC the proliferating NBL. From 17.5 dpc to birth (P0), expression became
CC restricted to the ganglion cell layer (GCL) and to the inner boundary
CC of the NBL (INL; inner nuclear layer), presumably the newly formed ACL
CC (amacrine cells). Predominantly expressed in post-mitotic cells in the
CC developing retina. Expressed from 9.5 dpc in the neural tube,
CC restricted to longitudinal ventral columns of neurons, extending from
CC the hindbrain to the caudal spinal cord. In the developing cortex, at
CC 12.5 dpc, expressed in the nascent cortical plate of the dorsal
CC telencephalon (at protein level). During peak production of deep layer
CC neurons between 12.5 and 13.5 dpc, restricted to postmigrational
CC neurons, with no expression in the proliferative ventricular zone (VZ)
CC or in migrating neurons. Between 15.5 and 17.5 dpc, when superficial
CC layer neurons are generated, strongly expressed in the cortical plate
CC and weakly in presumptive migrating neurons and in the subventricular
CC zone (SVZ). Does not colocalize with proliferating progenitors in S or
CC M phase in either the VZ or the SVZ; restricted to postmitotic
CC glutamatergic projection neurons during neurogenesis. Not detected in
CC cortical GABAergic interneurons or their extracortical sites of
CC genesis, the medial and caudal ganglionic eminences (at protein level).
CC Postnatally, down-regulation begins at the junction of the cingulate
CC cortex and neocortex; by postnatal day 4 (P4), down-regulation well
CC into the neocortex is observed anteriorly, with the exception of the
CC most superficial layer. At P4, expressed in neocortical layers II, III,
CC IV, and V. Within layer VI, expressed in only very rare scattered TBR1
CC negative neurons. Down-regulation continues from medial to lateral,
CC exhibiting a markedly reduced expression by P14. Expression varies
CC strikingly along the A-P axis with a precipitous decrease in the
CC rostral cortical plate. At 12.5 dpc, highly expressed medially in the
CC cingulate cortex with weak expression in the rest of the cortex. At
CC 15.5 dpc, expressed in a high caudomedial to a low rostrolateral
CC gradient. Between 15.5dpc and P0, expression increases laterally and
CC the gradient gradually transforms into a sharp border between the
CC presumptive rostral motor and sensory domains. During the first
CC postnatal week, there is a further transformation from homogeneous
CC expression across sensory cortex into discrete areas of high expression
CC coincident with the primary sensory areas. At P4 and P7, expressed in
CC primary visual cortex, primary auditory cortex and distinct primary
CC somatosensory representations, including the vibrissal barrel field. In
CC the spinal chord, transiently expressed in V1, V2, and dI6 interneurons
CC at 10.5 dpc. Also observed in a subpopulation of late-born neurons that
CC migrate to the superficial layers of the dorsal horn. Expression starts
CC shortly after the neurons exit mitosis at 13.5 dpc and persisting for
CC up to 2 weeks postnatally. At birth, about one-third of dorsal horn
CC neurons expressing the protein are excitatory and two-thirds
CC inhibitory. Also expressed in the developing eye and hair follicles, in
CC the epithelial layer of the cochlea in the developing inner, and in the
CC nasal epithelium. At 16.5 dpc, expressed outside the CNS, in particular
CC in all sensory organs; in the nasal pits, transcripts can be detected
CC in the olfactory epithelium. In the developing eye it can be found in
CC the inner and outer retinal layer, and it is also detectable in the
CC sensory layer of the cochlea in the developing inner ear. In addition,
CC expression is found in the developing hair follicles, both in the
CC epithelial component and in the dermal papilla, and in the skin.
CC {ECO:0000269|PubMed:14643684, ECO:0000269|PubMed:17092954,
CC ECO:0000269|PubMed:18957218, ECO:0000269|PubMed:20346763}.
CC -!- DISRUPTION PHENOTYPE: Null mice exhibits aberrant expression of brain
CC area-specific genes and structural organization in the somatosensory
CC and caudal motor cortices. In somatosensory cortex, vibrissal barrels
CC display postsynaptic disorganization. In caudal motor cortex, anomalous
CC differentiation of corticospinal motor neurons is observed, accompanied
CC by failure of corticospinal tract formation. Mice also develop self-
CC inflicted skin lesions and show significantly enhanced scratching
CC responses to pruritic agents, due to the selective loss of a subset of
CC spinal cord inhibitory interneurons. {ECO:0000269|PubMed:18957218,
CC ECO:0000269|PubMed:20346763}.
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DR EMBL; AF218865; AAF32324.1; -; mRNA.
DR EMBL; AK076228; BAC36262.1; -; mRNA.
DR EMBL; BC053007; AAH53007.1; -; mRNA.
DR CCDS; CCDS17253.1; -.
DR RefSeq; NP_067535.3; NM_021560.4.
DR AlphaFoldDB; Q8C6A8; -.
DR SMR; Q8C6A8; -.
DR STRING; 10090.ENSMUSP00000026120; -.
DR BindingDB; Q8C6A8; -.
DR PhosphoSitePlus; Q8C6A8; -.
DR PaxDb; Q8C6A8; -.
DR PRIDE; Q8C6A8; -.
DR ProteomicsDB; 273487; -.
DR DNASU; 59058; -.
DR GeneID; 59058; -.
DR KEGG; mmu:59058; -.
DR UCSC; uc008orl.2; mouse.
DR CTD; 27319; -.
DR MGI; MGI:1930001; Bhlhe22.
DR eggNOG; KOG3898; Eukaryota.
DR InParanoid; Q8C6A8; -.
DR OrthoDB; 1617813at2759; -.
DR PhylomeDB; Q8C6A8; -.
DR TreeFam; TF322733; -.
DR BioGRID-ORCS; 59058; 1 hit in 72 CRISPR screens.
DR PRO; PR:Q8C6A8; -.
DR Proteomes; UP000000589; Unplaced.
DR RNAct; Q8C6A8; protein.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0003682; F:chromatin binding; IDA:MGI.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IMP:MGI.
DR GO; GO:0042802; F:identical protein binding; IPI:MGI.
DR GO; GO:0046983; F:protein dimerization activity; IEA:InterPro.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; ISO:MGI.
DR GO; GO:0035881; P:amacrine cell differentiation; IMP:MGI.
DR GO; GO:0021960; P:anterior commissure morphogenesis; IMP:MGI.
DR GO; GO:0021952; P:central nervous system projection neuron axonogenesis; IMP:MGI.
DR GO; GO:0021796; P:cerebral cortex regionalization; IMP:MGI.
DR GO; GO:0021540; P:corpus callosum morphogenesis; IMP:MGI.
DR GO; GO:0021957; P:corticospinal tract morphogenesis; IMP:MGI.
DR GO; GO:0097154; P:GABAergic neuron differentiation; IMP:MGI.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:MGI.
DR GO; GO:0030182; P:neuron differentiation; IBA:GO_Central.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0060042; P:retina morphogenesis in camera-type eye; IMP:MGI.
DR GO; GO:0060040; P:retinal bipolar neuron differentiation; IMP:MGI.
DR Gene3D; 4.10.280.10; -; 1.
DR InterPro; IPR011598; bHLH_dom.
DR InterPro; IPR032654; Bhlhe22.
DR InterPro; IPR036638; HLH_DNA-bd_sf.
DR PANTHER; PTHR19290:SF52; PTHR19290:SF52; 1.
DR Pfam; PF00010; HLH; 1.
DR SMART; SM00353; HLH; 1.
DR SUPFAM; SSF47459; SSF47459; 1.
DR PROSITE; PS50888; BHLH; 1.
PE 1: Evidence at protein level;
KW Neurogenesis; Nucleus; Reference proteome; Repressor; Transcription;
KW Transcription regulation.
FT CHAIN 1..355
FT /note="Class E basic helix-loop-helix protein 22"
FT /id="PRO_0000274286"
FT DOMAIN 216..270
FT /note="bHLH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00981"
FT REGION 34..90
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 128..215
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CONFLICT 75
FT /note="R -> L (in Ref. 1; AAF32324)"
FT /evidence="ECO:0000305"
FT CONFLICT 149
FT /note="L -> R (in Ref. 1; AAF32324)"
FT /evidence="ECO:0000305"
FT CONFLICT 166
FT /note="R -> G (in Ref. 1; AAF32324)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 355 AA; 35217 MW; CA221A9169FCB897 CRC64;
MERGLHLGAA AASEDDLFLH KSLGTSAAKR LEAAFRSTPP GMDLSLAPPT RERPASSSSP
LGCFEPADPE GAGLRLPPPG GGGGASGGGG GVSVPGLLVG SAGVGGEPSL SSLPAGAALC
LKYGESAGRG SVAESSGGEQ SPDDDSDGLC ELVLRAGGPD PRASPRAGGG SAKVAEGCSN
AHLHGGSGLP PGGPTSGGGS GGGGGGSSKK SKEQKALRLN INARERRRMH DLNDALDELR
AVIPYAHSPS VRKLSKIATL LLAKNYILMQ AQALEEMRRL VAYLNQGQAI SAASLPSSAA
AAAAAAALHP ALGAYEQAAG YPFSAGLPPA ASCPEKCALF NSVSSSLCKQ CTEKP
