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måndag 10 juli 2023

Tiamiinista . Tiamiinipyrofosfokinaasi1 TPK1 tuottaa tiamiinitrifosfaattia. Sitä muodostuu myös Adenylaattikinaasi1:ll sytosolissa tai FoF1-ATP syntaasilla aivomitokondrioissa.



 The phosphorylation of thiamine (B1)  occurs by two main enzymes: thiamine diphosphokinase, which catalyzes the formation of thiamine pyrophosphate (TPP) using ATP, 




NCBI Gene Summary for TPK1 Gene

  • The protein encoded by this gene functions as a homodimer and catalyzes the conversion of thiamine (B1)  to thiamine pyrophosphate (ThDP) , a cofactor for some enzymes of the glycolytic and energy production pathways. Defects in this gene are a cause of thiamine metabolism dysfunction syndrome-5. [provided by RefSeq, Apr 2017]

GeneCards Summary for TPK1 Gene

TPK1 (Thiamin Pyrophosphokinase 1) is a Protein Coding gene. Diseases associated with TPK1 include Thiamine Metabolism Dysfunction Syndrome 5 and Childhood Encephalopathy Due To Thiamine Pyrophosphokinase Deficiency. Among its related pathways are Metabolism of water-soluble vitamins and cofactors and Metabolism. Gene Ontology (GO) annotations related to this gene include kinase activity and thiamine binding


LÄHDE: Martin A. Crook, in Laboratory Assessment of Vitamin Status, 2019


Thiamine TPP is produced by thiamine diphosphokinase and is an essential cofactor for the decarboxylation of 2-oxoacids, such as the conversion of pyruvate to acetyl coenzyme a and also other pathways including pyruvate dehydrogenase (PDH), α-ketogluterate dehydrogenase (KGDH), and branched-chain α-keto acid dehydrogenase (BCKDH), (Fig. 6.2). In thiamine deficiency, pyruvate cannot be metabolized and accumulates in the blood. Thiamine TPP is also an essential cofactor for transketolase in the pentose-phosphate pathway

Thiamine is essential for the optimal function of the nervous system and repair of myelin nerve sheaths. In turn magnesium is an important cofactor for thiamine-dependent enzymes.2–9 In addition, other reputed noncofactor roles of thiamine compounds are shown within the oxidative stress response, gene regulation, cholinergic system, immune function, chloride channels, and neurotransmission.2–6

 LÄHDE: Barbara Plecko, Robert Steinfeld, in Swaiman's Pediatric Neurology (Sixth Edition), 2017

Thiamine Pyrophosphokinase Deficiency

Autosomal-recessive thiamine pyrophosphokinase deficiency (OMIM 606370) presents with a late-onset Leigh-like disease and basal ganglia changes on MRI. During acute episodes, elevated blood and CSF lactate and enhanced excretion of α-ketoglutarate are consistent findings. Thiamine pyrophosphate (TPP) concentrations in blood and muscle are reduced, and diagnosis is confirmed by sequencing of the TPK1 gene. Thiamine supplementation at 100- to 200 mg/day was of limited benefit in symptomatic patients. Earlier intervention with doses around 500 mg/day may be associated with better prognosis.

LÄHDE: GeneGards:

TPK1 , Thiamin pyrophosphokinase 1 ,  (7q35)

Orphanet: 58 Childhood encephalopathy due to thiamine pyrophosphokinase (TPK1) deficiency is a rare inborn error of metabolism disorder characterized by early-onset, acute, encephalopathic episodes (frequently triggered by viral infections), associated with lactic acidosis and alpha-ketoglutaric aciduria, which typically manifest with variable degrees of ataxia, generalized developmental regression (which deteriorates with each episode) and dystonia. Other manifestations include spasticity, seizures, truncal hypotonia, limb hypertonia, brisk tendon reflexes and reversible coma.

MalaCards based summary: Childhood Encephalopathy Due to Thiamine Pyrophosphokinase Deficiency and has symptoms including ataxia and muscle spasticity. An important gene associated with Childhood Encephalopathy Due to Thiamine Pyrophosphokinase Deficiency is TPK1 (Thiamin Pyrophosphokinase 1). Affiliated tissues include whole blood and brain.


doi: 10.1007/s11011-014-9509-4. Epub 2014 Mar 4.

Thiamine triphosphate: a ubiquitous molecule in search of a physiological role


Thiamine triphosphate (ThTP) was discovered over 60 years ago and it was long thought to be a specifically neuroactive compound. Its presence in most cell types, from bacteria to mammals, would suggest a more general role but this remains undefined. In contrast to thiamine diphosphate (ThDP), ThTP is not a coenzyme. In E. coli cells, ThTP is transiently produced in response to amino acid starvation, while in mammalian cells, it is constitutively produced at a low rate. Though it was long thought that ThTP was synthesized by a ThDP:ATP phosphotransferase, more recent studies indicate that it can be synthesized by two different enzymes: (1) adenylate kinase 1 in the cytosol and (2) FoF1-ATP synthase in brain mitochondria. Both mechanisms are conserved from bacteria to mammals. Thus ThTP synthesis does not seem to require a specific enzyme. In contrast, its hydrolysis is catalyzed, at least in mammalian tissues, by a very specific cytosolic thiamine triphosphatase (ThTPase), controlling the steady-state cellular concentration of ThTP. In some tissues where adenylate kinase activity is high and ThTPase is absent, ThTP accumulates, reaching ≥ 70% of total thiamine, with no obvious physiological consequences. In some animal tissues, ThTP was able to phosphorylate proteins, and activate a high-conductance anion channel in vitro. These observations raise the possibility that ThTP is part of a still uncharacterized cellular signaling pathway. On the other hand, its synthesis by a chemiosmotic mechanism in mitochondria and respiring bacteria might suggest a role in cellular energetics.

ALS/FTD etiologiasta


. 2021 May 31;30(11):971-984.
doi: 10.1093/hmg/ddab073.
ALS/FTD-causing mutation in cyclin F causes the dysregulation of SFPQ
Previously, we identified missense mutations in CCNF that are causative of familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Hallmark features of these diseases include the build-up of insoluble protein aggregates as well as the mislocalization of proteins such as transactive response DNA binding protein 43 kDa (TDP-43). In recent years, the dysregulation of SFPQ (splicing factor proline and glutamine rich) has also emerged as a pathological hallmark of ALS/FTD. 
CCNF encodes for the protein cyclin F, a substrate recognition component of an E3 ubiquitin ligase. We have previously shown that ALS/FTD-linked mutations in CCNF cause disruptions to overall protein homeostasis that leads to a build-up of K48-linked ubiquitylated proteins as well as defects in autophagic machinery. To investigate further processes that may be affected by cyclin F, we used a protein-proximity ligation method, known as Biotin Identification (BioID), standard immunoprecipitations and mass spectrometry to identify novel interaction partners of cyclin F and infer further process that may be affected by the ALS/FTD-causing mutation. Results demonstrate that cyclin F closely associates with proteins involved with RNA metabolism as well as a number of RNA-binding proteins previously linked to ALS/FTD, including SFPQ. Notably, the overexpression of cyclin F(S621G) led to the aggregation and altered subcellular distribution of SFPQ in human embryonic kidney (HEK293) cells, while leading to altered degradation in primary neurons. Overall, our data links ALS/FTD-causing mutations in CCNF to converging pathological features of ALS/FTD and provides a link between defective protein degradation systems and the pathological accumulation of a protein involved in RNA processing and metabolism.
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söndag 9 juli 2023

Yleistynyt amylomyotrofia

Retinan  regulatiivisen genomin säätelygeenien joukosta  TCF4  omaa  onkogeenisyyden alueella assoisaatiota  yleistyneeseenamyotrofiaan ja mm. geeniin VAMP1. https://www.genecards.org/cgi-bin/carddisp.pl?gene=TCF4&keywords=TCF4

Generalized amyotrophy HP:0003700

Generalized (diffuse, unlocalized) amyotrophy (muscle atrophy) affecting multiple muscles.



Synonyms:    Diffuse amyotrophy, Diffuse muscle atrophy, Diffuse muscle wasting, Diffuse skeletal 


muscle wasting, Generalised amyotrophy, Generalised muscle atrophy, Generalised muscle degeneration, Generalized muscle atrophy, Generalized muscle degeneration, Muscle atrophy, diffuse, Muscle atrophy, generalised, Muscle atrophy, generalized, Muscular atrophy, generalised, Muscular atrophy, generalized

OMIM:610006  2-Methylbutyryl-Coa dehydrogenase deficiency ACADSB [36 ]

ORPHA:466794Acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome SCYL1 [57410 ]

OMIM:300523 Allan-Herndon-Dudley syndrome SLC16A2 [6567 ]

ORPHA:79279 Alpha-N-acetylgalactosaminidase deficiency type 1 NAGA [4668 ]

ORPHA:157954 ANE syndrome RBM28 [55131 ]

ORPHA:251282 Autosomal dominant spastic ataxia type 1, VAMP1 [6843 ]

Gene Location: 12p13.31

Synapotobrevins, syntaxins, and the synaptosomal-associated protein SNAP25 are the main components of a protein complex involved in the docking and/or fusion of synaptic vesicles with the presynaptic membrane. The protein encoded by this gene is a member of the vesicle-associated membrane protein (VAMP)/synaptobrevin family. Mutations in this gene are associated with autosomal dominant spastic ataxia 1. Multiple alternative splice variants have been described, but the full-length nature of some variants has not been defined. [provided by RefSeq, Jul 2014]


 Onko  jotain yhteyttä  VAMP1 geenin jollain  geenimutaatiolla  aikuisuudessa ilmenevään amyotrofiseen lateroskleroosiin?


HAKU PubMwd  

Neuronal overexpression of human VAPB slows motor impairment and neuromuscular denervation in a mouse model of ALS.
Kim JY, Jang A, Reddy R, Yoon WH, Jankowsky JL. Hum Mol Genet. 2016 Nov 1;25(21):4661-4673. doi: 10.1093/hmg/ddw294. PMID: 28173107 Free PMC article.
Four mutations in the VAMP/synaptobrevin-associated protein B (VAPB) gene have been linked to amyotrophic lateral sclerosis (ALS) type 8. The mechanism by which VAPB mutations cause motor neuron disease is unclear, but studies of the most common P56S variant suggest both loss of function and dominant-negative sequestration of wild-type protein. Diminished levels of VAPB and its proteolytic cleavage fragment have also been reported in sporadic ALS cases, suggesting that VAPB loss of function may be a common mechanism of disease. Here, we tested whether neuronal overexpression of wild-type human VAPB would attenuate disease in a mouse model of familial ALS1. We used neonatal intraventricular viral injections to express VAPB or YFP throughout the brain and spinal cord of superoxide dismutase (SOD1) G93A transgenic mice. Lifelong elevation of neuronal VAPB slowed the decline of neurological impairment, delayed denervation of hindlimb muscles, and prolonged survival of spinal motor neurons. Collectively, these changes produced a slight but significant extension in lifespan, even in this highly aggressive model of disease. Our findings lend support for a protective role of VAPB in neuromuscular health. 

SILMÄN varhaiskehityksestä

Integrative Single-Cell Transcriptomics and Epigenomics Mapping of the Fetal Retina Developmental Dynamics

First published: 05 April 2023

The underlying mechanisms that determine gene expression and chromatin accessibility in retinogenesis are poorly understood. Herein, single-cell RNA sequencing and single-cell assay for transposase-accessible chromatin sequencing are performed on human embryonic eye samples obtained 9–26 weeks after conception to explore the heterogeneity of retinal progenitor cells (RPCs) and neurogenic RPCs. The differentiation trajectory from RPCs to 7 major types of retinal cells are verified. Subsequently, diverse lineage-determining transcription factors are identified and their gene regulatory networks are refined at the transcriptomic and epigenomic levels. Treatment of retinospheres, with the inhibitor of RE1 silencing transcription factor, X5050, induces more neurogenesis with the regular arrangement, and a decrease in Müller glial cells. The signatures of major retinal cells and their correlation with pathogenic genes associated with multiple ocular diseases, including uveitis and age-related macular degeneration are also described. A framework for the integrated exploration of single-cell developmental dynamics of the human primary retina is provided.

 The eye is a vital and highly specialized visual organ, and the retina is the most important component of vision production in the eye. The retina primarily comprises six types of neurons and several types of glial cells. 

Therein, photoreceptor cells, including cones and rods in the outer nuclear layer (ONL), receive and process light signals from the external environment. 

The interneurons, including amacrine cells (ACs), bipolar cells (BCs), and horizontal cells (HCs) in the inner plexiform layer (IPL), inner nuclear layer (INL), and outer plexiform layer (OPL), deliver signals from the photoreceptor cells to retinal ganglion cells (RGCs) in the ganglion cell layer (GCL). 

Inside the RGCs, these light signals are converted to electrical signals and transmitted to the brain.[1] 

The primary types of retinal glial cells include Müller glial cells (MGCs) and microglia

MGCs mainly act as mediators to assist photoreceptor cells in light absorption, provide nutrients to neurons, and remove metabolic waste,[2, 3] 

 whereas microglia are resident immune cells in the retina and central nervous system that have a critical role in the maintenance of normal homeostasis and immune surveillance of these systems.[4]

The retina primarily develops from retinal progenitor cells (RPCs), which differentiate into six classes of neurons and one class of glial cells at chronologically separate, yet frequently overlapping, intervals during development. Before becoming terminal cells, RPCs typically transition through a precursor cell stage. Distinct evolutionary fates are selected as the RPCs reach saddle points, where they segregate into different and progressively restricted precursor cell states and finally develop and mature into terminal cells.[5-9] Although terminal-cell specification has received considerable attention, it remains unclear how heterogeneity develops within RPCs.

The general process of retinal development is meticulously regulated by cell-type-specific transcription factors (TFs) that recruit chromatin effectors to repurpose the chromatin and promote new retinal cellular characteristics.[10] 

 Dysregulation of any step in this process can cause varying degrees of visual dysfunction and congenital diseases, including retinoblastoma, Leber congenital amaurosis, and autosomal recessive retinitis pigmentosa.[10-13] 

 Meanwhile, the development of retinal cell lineages remains to be investigated, and prospective critical factors have not yet been thoroughly characterized.

Recently, the single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) and single-cell RNA sequencing (scRNA-seq) have proven effective for the analysis of human embryonic retinal development. More specifically, scRNA-seq has been employed to investigate the differentiation trajectory of RPCs and unique subpopulations of embryonic retinal cells. The associated studies have reported that myriad TFs have crucial roles in directing the development of specific lineages, such as nuclear factor I (NFI) in the regulation of cell-cycle exit and generation of late-born retinal cell types, and atonal bHLH transcription factor 7 (ATOH7) in the specification of cone photoreceptors.[14-17] 

Meanwhile, gene expression patterns of important lineage-defined TFs are primarily regulated by epigenetic programs that are influenced by changes in chromatin accessibility and can be detected by scATAC-seq. For instance, the sequences of various TF cascades responsible for determining cell fate have been verified at the epigenomic level from a developing human retina database using scATAC-seq.[18-20] However, integrated scRNA-seq and scATAC-seq datasets from the same human embryonic eye sample are lacking; hence, transcriptomic and epigenetic results have the potential to be better matched.

Here, we performed an integrative analysis of scATAC-seq and scRNA-seq on individual cells obtained from human embryonic eyes to capture the dynamic transcriptomic and epigenetic landscapes of the developing human eye at single-cell resolution. 

To this end, we probed the precursors of MGCs and the intrinsic connection among neurogenic RPCs (NPCs).

 We then constructed developmental trajectories and gene regulatory networks (GRNs) for RPC-derived cells. (Figure1A).

 In this way, we defined the continuous evolution of TF motif activity related to neuronal specification and identified the co-dependence of TF motif accessibility along these trajectories.

 By investigating whether RE1 silencing transcription factor (REST) influences RPC and MGC fate, we found that treatment of retinospheres with a REST inhibitor induced neurogenesis with a regular spatial arrangement and decrease in MGCs. 

Finally, we identified differences between embryonic macrophages and microglia and combined disease-related genes from retina-related diseases to characterize relationships between risk factors and specific retinal cell types. 

 Collectively, this study highlights neurogenic cell fate determination processes and elucidates a portion of the gene regulation involved in retinal development.



A single-cell regulatory atlas of the developing human retina. A) Schematic of experimental design. B) Retinal structure schematic. C) Immunofluorescence analysis of primary human retinal tissue validating the expression of cell-type-specific markers, including NRL (rods); RGR (MGCs); CALIBINDIN (HCs); PKC (BCs); CALRETININ (HCs, ACs, and RGCs); and BRN3A (RGCs). Nuclei are counterstained with DAPI. Scale bar, 50 µm. D) UMAP embedding of the retina scRNA-seq dataset, with individual cells colored by age and annotated cell types. E) Violin plot showing relative expression of transcripts with high specificity for individual cell types ordered by cell type. F) UMAP embedding of the retina scATAC-seq dataset, with individual cells colored by age and annotated cell types. G) Coverage plots and gene score of known marker genes for cell types. Gene color representing the direction of gene translation (red: right; blue: left). H) UMAP embedding of the developmental trajectories of RPCs, MGCs, and NPCs colored by pseudo-time. Red arrows show two developmental directions from RPCs. I) UMAP embedding of the developmental trajectories of RPCs and RPC-derived cells from scRNA-seq colored by pseudo-time. White arrows show three neuronal lineages. Abbreviations: PCW, post-conception weeks; RGCs, retinal ganglion cells; HCs, horizontal cells; ACs, amacrine cells; BCs, bipolar cells; MGCs, Müller glial cells; GCL, ganglion cell layer; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer.
Figure 2 Transcriptomic and epigenetic patterns of GRNs in RPCs and their derived cells. Heatmap of A) transcriptional expression, B) gene activity, and C) their motif enrichment score of

 Using scRNA-seq, most cells were divided into 17 groups according to the normalized expression of known markers (Figure 1D,E; Table S2, Supporting Information). Due to the limited number of MGCs (38 cells, 0.0505% of total cell count) and microglia (11 cells, 0.0146% of total cell count) directly mapped to the chromatin landscape in scRNA-seq, subsequent analysis was not performed (Tables S3 and S4, Supporting Information). We then integrated the gene expression levels with corresponding gene activity scores and found that major cluster annotations in the retina of matched cells were consistent. A group of RPCs expressing CCND1, HES1, and SOX2 was identified, and several NPC markers, including ATOH7, HES6, and DLL3, were expressed by cells in one scRNA-seq cluster. Additionally, a group of RGCs expressing NEFM, SNCG, and GAP43, as well as genes related to HC identification (ONECUT1 and ONECUT2), was detected. Moreover, a group of cells expressing AC-related genes (GAD2 and TFAP2A) was observed. Among the BC clusters, a group of cells expressing VSX1 and TMEM215, and distinct clusters of photoreceptor cells, including cones (expressing PRDM1 and THRB) and rods (expressing NRL, RHO) were detected. We further annotated a cluster of cells highly expressing RGR, GPX3, and RLBP1 as MGCs and determined that RGR might be more specific to MGCs than RLBP1 during the embryonic period. Furthermore, we observed gene expression in clusters of retinal pigment epithelia (RPE) (RPE65 and TTR), fibroblasts (DCN and MGP), melanocytes (PMEL and TYRP1), endothelial cells (PECAM1 and ENG), lens cells (CRYGC and LIM2), and corneal epithelium (KRT5). Numerous markers exhibited dynamic gene activity scores in related scATAC-seq clusters (Figure 1F,G). The emergence of these major retinal cell types reflected normal retinal development (Figure S1A, Supporting Information).

Considering that RPCs have a two-branch developmental tendency, including glial cell orientation and neuronal orientation,[6, 14, 16] we extracted RPCs, NPCs, and MGCs, as well as six major neurons for pseudo-time analysis via two different approaches (Palantir and Monocle3). The results verified that RPCs could differentiate into glia or NPCs, and transitional NPCs could develop into neurons of three lineages (Figure 1H,I; Figure S1B, Supporting Information).

Collectively, we generated a collaborative database that describes retinal development, laying the groundwork for subsequent analyses.

Construction of Gene Regulatory Networks in Retinal Progenitor Cell-Producing Cells at the Transcriptomic and Epigenetic Levels

To identify which TFs are crucial for the differentiation of RPCs into major retinal cells and for the maintenance of their specific cell end-states, we performed Python implementation of a single-cell regulatory network of inference and clustering (SCENIC) analysis. Moreover, we assessed the relative accessibility to chromatin and enrichment of motifs for these TFs (Figure 2).

The results predicted a series of TFs, with highly similar transcriptomic and epigenomic levels, as vital for the fate of specific cell types (Figure 2A–C; Figure S2A, Supporting Information). UMAP embedding of SCENIC TF activity revealed four developmental branch endpoints derived from RPCs, which were demarcated and represented by respective TFs reported to affect the development of related lineages (Figure 2D), such as SOX8 for the MGC lineage, POU4F3 for RGC lineage, TFAP2B for HC/AC lineage, and LHX4 and NEUROD1 for BC/PH lineage.[21, 23-25]

Next, we screened critical cell-type-specific TFs at the epigenetic level from the top predicted TFs; the 10 genes regulated by at least two key TFs, according to the weight value, were selected to depict the top GRNs of related TFs for each cell linage (Figure 2E; Figure S2B,C, Supporting Information). For instance, the Iroquois homeobox protein family TFs (IRX1 and IRX2) exhibited a marked influence on genes required for RGC development, such as EBF3, NRN1, and NEFL,[26, 22] whereas ONECUT family members had regulatory effects on HC/AC lineage-specific factors, including PROX1 and BARHL2.[27-29]

In summary, we identified fate-determining TFs for RPCs and their products, constructed.... more  in link


SILMÄ , Retinogeneesin varhaiset vaiheet ja genominen säätelyverkosto

 Retinasolujen regulatorisista geeneistä  haku:


3 articles found by citation matching

doi: 10.1002/dneu.22188. Epub 2014 May 22. Transcriptome of Atoh7 retinal progenitor cells identifies new Atoh7-dependent regulatory genes for retinal ganglion cell formation
Affiliations DOI: 10.1002/dneu.22188

Free PMC article


 RPC= Retinal Progenitor Cells 
 Atoh-expressing retinal progenitor cells (RPC ) can give rise to all retinal cell types
bHLH transcription factor ATOG7(Math5)  essential  for establishing RGC fate.
RGC= retinal Ganglion Cells, earliest type to differentiate,
Atoh7-expressing subpopulation of  RPC  commits to an  RGC fate. 
Transcriptional regulator
Ebf3This gene encodes a member of the early B-cell factor (EBF) family of DNA binding transcription factors. EBF proteins are involved in B-cell differentiation, bone development and neurogenesis, and may also function as tumor suppressors. The encoded protein inhibits cell survival through the regulation of genes involved in cell cycle arrest and apoptosis, and aberrant methylation or deletion of this gene may play a role in multiple malignancies including glioblastoma multiforme and gastric carcinoma. [provided by RefSeq, Sep 2011]GeneCards Summary for EBF3 GeneEBF3 (EBF Transcription Factor 3) is a Protein Coding gene. Diseases associated with EBF3 include Hypotonia, Ataxia, And Delayed Development Syndrome and Neurogenic Bladder. Among its related pathways are Differentiation of white and brown adipocyte. Gene Ontology (GO) annotations related to this gene include protein dimerization activity. An important paralog of this gene is EBF1.UniProtKB/Swiss-Prot Summary for EBF3 Gene Transcriptional activator (PubMed:28017373, 28017372, 28017370). Recognizes variations of the palindromic sequence 5'-ATTCCCNNGGGAATT-3' (By similarity). ( COE3_HUMAN,Q9H4W6 )
EYA2, eyes absent homolog 2,  early target gene of ATOH7,    RGC specification. Functions both as protein phosphatase and as transcriptional coactivator for SIX1, and probably also for SIX2, SIX4 and SIX5 (PubMed:12500905, 23435380). Tyrosine phosphatase that dephosphorylates 'Tyr-142' of histone H2AX (H2AXY142ph) and promotes efficient DNA repair via the recruitment of DNA repair complexes containing MDC1. 'Tyr-142' phosphorylation of histone H2AX plays a central role in DNA repair and acts as a mark that distinguishes between apoptotic and repair responses to genotoxic stress (PubMed:19351884). Its function as histone phosphatase may contribute to its function in transcription regulation during organogenesis. Plays an important role in hypaxial muscle development together with SIX1 and DACH2; in this it is functionally redundant with EYA1
Pax6-Atoh7-Eya2 pathway
Differentiation factor  Pou4f2 (Brain-Specific Homeobox/POU Domain Protein 3BThe protein encoded by this gene is a member of the POU-domain transcription factor family and may be involved in maintaining visual system neurons in the retina. The level of the encoded protein is also elevated in a majority of breast cancers, resulting in accelerated tumor growth. [provided by RefSeq, Sep 2011] Tissue-specific DNA-binding transcription factor involved in the development and differentiation of target cells (PubMed:19266028, 23805044). Functions either as activator or repressor modulating the rate of target gene transcription through RNA polymerase II enzyme in a promoter-dependent manner (PubMed:19266028, 23805044). Binds to the consensus octamer motif 5'-AT[A/T]A[T/A]T[A/T]A-3' of promoter of target genes. Plays a fundamental role in the gene regulatory network essential for retinal ganglion cell (RGC) differentiation. Binds to an octamer site to form a ternary complex with ISL1; cooperates positively with ISL1 and ISL2 to potentiate transcriptional activation of RGC target genes being involved in RGC fate commitment in the developing retina and RGC axon formation and pathfinding. Inhibits DLX1 and DLX2 transcriptional activities preventing DLX1- and DLX2-mediated ability to promote amacrine cell fate specification. In cooperation with TP53 potentiates transcriptional activation of BAX promoter activity increasing neuronal cell apoptosis. Negatively regulates BAX promoter activity in the absence of TP53. Acts as a transcriptional coactivator via its interaction with the transcription factor ESR1 by enhancing its effect on estrogen response element (ERE)-containing promoter. Antagonizes the transcriptional stimulatory activity of POU4F1 by preventing its binding to an octamer motif. Involved in TNFSF11-mediated terminal osteoclast differentiation (By similarity). ( PO4F2_HUMAN,Q12837 )https://www.genecards.org/cgi-bin/carddisp.pl?gene=POU4F2&keywords=Pou4f2


The bHLH transcription factor ATOH7 (Math5) is essential for establishing retinal ganglion cell (RGC) fate. However, Atoh7-expressing retinal progenitor cells (RPCs) can give rise to all retinal cell types, suggesting that other factors are involved in specifying RGCs. The basis by which a subpopulation of Atoh7-expressing RPCs commits to an RGC fate remains uncertain but is of critical importance to retinal development since RGCs are the earliest cell type to differentiate

To better understand the regulatory mechanisms leading to cell-fate specification, a binary genetic system was generated to specifically label Atoh7-expressing cells with green fluorescent protein (GFP). Fluorescence-activated cell sorting (FACS)-purified GFP(+) and GFP(-) cells were profiled by RNA-seq. Here, we identify 1497 transcripts that were differentially expressed between the two RPC populations. 

Pathway analysis revealed diminished growth factor signaling in Atoh7-expressing RPCs, indicating that these cells had exited the cell cycle. In contrast, axon guidance signals were enriched, suggesting that axons of Atoh7-expressing RPCs were already making synaptic connections. Notably, many genes enriched in Atoh7-expressing RPCs encoded transcriptional regulators, and several were direct targets of ATOH7, including, and unexpectedly, Ebf3 and Eya2

We present evidence for a Pax6-Atoh7-Eya2 pathway that acts downstream of Atoh7 but upstream of differentiation factor Pou4f2.

 EYA2 is a protein phosphatase involved in protein-protein interactions and posttranslational regulation. These properties, along with Eya2 as an early target gene of ATOH7, suggest that EYA2 functions in RGC specification. Our results expand current knowledge of the regulatory networks operating in Atoh7-expressing RPCs and offer new directions for exploring the earliest aspects of retinogenesis.

Keywords: Atoh7/Math5; eyes absent homolog2; gene regulatory network; retinal ganglion cells; retinal progenitor cells.

© 2014 Wiley Periodicals, Inc. 
This intronless gene encodes a member of the basic helix-loop-helix family of transcription factors, with similarity to Drosophila atonal gene that controls photoreceptor development. Studies in mice suggest that this gene plays a central role in retinal ganglion cell and optic nerve formation. Mutations in this gene are associated with nonsyndromic congenital retinal nonattachment. [provided by RefSeq, Dec 2011].
Transcription factor that binds to DNA at the consensus sequence 5'-CAG[GC]TG-3' (PubMed:31696227). Dimerization with TCF3 isoform E47 may be required in certain situations (PubMed:31696227). Binds to gene promoters and enhancer elements, and thereby regulates a transcriptional program of retinal ganglion cell (RGC) determinant genes (By similarity). Although the exact mechanism is not certain, retinal transcription regulation by ATOH7 has a role in RGC determination and survival, photoreceptor population development, targeting of RGC axons to the optic nerve and development of the retino-hypothalamic tract (By similarity). Binds to its own promoter and enhancer sequences, suggesting autoregulation of ATOH7 transcription (By similarity). Required for retinal circadian rhythm photoentrainment (By similarity). Plays a role in brainstem auditory signaling and binaural processing (By similarity). ( ATOH7_HUMAN,Q8N100 )-
(Human Phenotype Ontology for ATOH7 Gene


Interacting Proteins for ATOH7 Gene_ TCF members

STRING Interaction Network Preview (showing top 5 STRING interactants - click image to see top 25) 
TCF3 [ENSP00000262965]
 Transcription factor E2-alpha; Transcriptional regulator. Involved in the initiation of neuronal differentiation. Heterodimers between TCF3 and tissue- specific basic helix-loop-helix (bHLH) proteins play major roles in determining tissue-specific cell fate during embryogenesis, like muscle or early B-cell differentiation. Dimers bind DNA on E- box motifs: 5'-CANNTG-3'. Binds to the kappa-E2 site in the kappa immunoglobulin gene enhancer. Binds to IEB1 and IEB2, which are short DNA sequences in the insulin gene transcription control region
 TCF4 [ENSP00000381382]
 Transcription factor 4; Transcription factor that binds to the immunoglobulin enchancer Mu-E5/KE5-motif. Involved in the initiation of neuronal differentiation. Activates transcription by binding to the E box (5'-CANNTG-3'). Binds to the E-box present in the somatostatin receptor 2 initiator element (SSTR2-INR) to activate transcription (By similarity). Preferentially binds to either 5'-ACANNTGT-3' or 5'-CCANNTGG-3'; Basic helix-loop-helix proteins 
Transcription factor 12;
 Transcriptional regulator. Involved in the initiation of neuronal differentiation. Activates transcription by binding to the E box (5'-CANNTG-3'); Basic helix-loop-helix proteins
Identifier: ENSP00000388940, TCF12

TCF3 This gene encodes a member of the E protein (class I) family of helix-loop-helix transcription factors. E proteins activate transcription by binding to regulatory E-box sequences on target genes as heterodimers or homodimers, and are inhibited by heterodimerization with inhibitor of DNA-binding (class IV) helix-loop-helix proteins. E proteins play a critical role in lymphopoiesis, and the encoded protein is required for B and T lymphocyte development. Deletion of this gene or diminished activity of the encoded protein may play a role in lymphoid malignancies. This gene is also involved in several chromosomal translocations that are associated with lymphoid malignancies including pre-B-cell acute lymphoblastic leukemia (t(1;19), with PBX1), childhood leukemia (t(19;19), with TFPT) and acute leukemia (t(12;19), with ZNF384). Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the short arm of chromosome 9. [provided by RefSeq, Sep 2011]

TCF3 (Transcription Factor 3) is a Protein Coding gene. Diseases associated with TCF3 include Agammaglobulinemia 8B, Autosomal Recessive and Agammaglobulinemia 8A, Autosomal Dominant. Among its related pathways are Gene expression (Transcription) and ERK Signaling. Gene Ontology (GO) annotations related to this gene include DNA-binding transcription factor activity and sequence-specific DNA binding. An important paralog of this gene is TCF12.

UniProtKB/Swiss-Prot Summary for TCF3 Gene
Transcriptional regulator involved in the initiation of neuronal differentiation and mesenchymal to epithelial transition (By similarity). Heterodimers between TCF3 and tissue-specific basic helix-loop-helix (bHLH) proteins play major roles in determining tissue-specific cell fate during embryogenesis, like muscle or early B-cell differentiation (By similarity). Together with TCF15, required for the mesenchymal to epithelial transition (By similarity). Dimers bind DNA on E-box motifs: 5'-CANNTG-3' (By similarity). Binds to the kappa-E2 site in the kappa immunoglobulin gene enhancer (PubMed:2493990). Binds to IEB1 and IEB2, which are short DNA sequences in the insulin gene transcription control region (By similarity). ( TFE2_HUMAN,P15923 )

[Isoform E47]: Facilitates ATOH7 binding to DNA at the consensus sequence 5'-CAGGTG-3', and positively regulates transcriptional activity. ( TFE2_HUMAN,P15923 )


Aliases for TCF3 Gene
  • GeneCards Symbol: TCF3 2
  • Transcription Factor 3 2 3 4 5
  • BHLHb21 2 3 4 5
  • ITF1 2 3 4 5
  • E2A 2 3 4 5
  • Immunoglobulin Transcription Factor 1 2 3 4
  • Transcription Factor E2-Alpha 2 3 4
  • Kappa-E2-Binding Factor 2 3 4
  • VDIR 2 3 5
  • E47 2 3 5
  • P75 2 3 5
  • Class B Basic Helix-Loop-Helix Protein 21 3 4
  • Transcription Factor ITF-1 3 4
  • VDR Interacting Repressor 2 3
  • MGC129647 2 5
  • MGC129648 2 5
  • TCF-3 3 4
  • Transcription Factor 3 (E2A Immunoglobulin Enhancer Binding Factors E12/E47) 3
  • Negative Vitamin D Response Element-Binding Protein 3
  • E2A Immunoglobulin Enhancer-Binding Factor E12/E47 2
  • Immunoglobulin Enhancer-Binding Factor E12/E47 4
  • Vitamin D Receptor-Interacting Repressor 3
  • E2A-HLF Fusion Transcript Protein 3
  • Helix-Loop-Helix Protein HE47 3
  • NOL1-TCF3 Fusion 3
  • BHLHB21 4
  • AGM8A 3
  • AGM8B 3 AGM8