Disease relevance of HOMER1

• All transgenic mice develop bilateral intraocular retinal tumors in the inner nuclear layer with Homer Wright-like rosettes, and one quarter develop midbrain tumors resembling trilateral retinoblastoma [1].
• Today James Homer Wright is remembered and honored 100 years after his description of the stain that, along with the pseudorosettes of neuroblastoma, carry his name into eternity and ensure his great contributions will never be forgotten [2].
• Immunohistochemical and ultrastructural observations on Homer Wright (neuroblastic) rosettes and the "pale islands" of human cerebellar medulloblastomas [3].
• Racing Homer pigeons were found to be more resistant to aortic atherosclerosis and more susceptible to coronary atherosclerosis than White Carneau pigeons [4].
• The tumors were composed of small uniform cells possessing amitotic round nuclei with frequent perinuclear halos, a few Homer Wright rosettes and no ganglion cells; an appearance resembling that of oligodendroglioma [5].

Psychiatry related information on HOMER1

• We are currently screening transduction gene polymorphisms (14-3-3 epsilon, GNB3, HOMER1, Akt1) in a large sample of patients with DSM-IV diagnosis of schizophrenia and bipolar disorder assessed for suicide behaviour [6].

High impact information on HOMER1

• Agonist-independent activation of metabotropic glutamate receptors by the intracellular protein Homer [7].
• We demonstrate physiologic binding of PIKE-L to Homer, an adaptor protein known to link metabotropic glutamate receptors to multiple intracellular targets including the inositol 1,4,5-trisphosphate receptor (IP3R) [8].
• PI3 kinase enhancer-Homer complex couples mGluRI to PI3 kinase, preventing neuronal apoptosis [8].
• Converging preclinical observations indicate a potential role for both immediate early gene Homer isoforms and constitutively expressed Homer isoforms in behavioral pathologies associated with neuropsychiatric disorders, such as addiction and/or alcoholism, depression, anxiety, epilepsy and schizophrenia [9].
• Binding of IP(3) to the IP(3)Rs dissociates the interaction between IP(3)Rs and H1 but not between H1 and TRPC3 to form IP(3)Rs-TRPC3-H1b/c. TIRFM and biotinylation assays show robust receptor- and store-dependent translocation of the TRPC3 to the PM and their retrieval upon termination of cell stimulation [10].

Chemical compound and disease context of HOMER1

• Specific immunohistochemical localization of lactate dehydrogenase (LDH isoenzyme 1) in well-differentiated retinoblastomas revealed the presence of this enzyme predominantly in the cytoplasm of cells that form Flexner-Wintersteiner and Homer Wright rosettes [11].

Biological context of HOMER1

• We have discovered that extensive alternative splicing generates a family of 17 Homer proteins [12].
• In the present study, we demonstrate that Homer 1b (H1b), a constitutively expressed splice form of the immediate early gene product Homer (now termed Homer 1a) regulates the trafficking and surface expression of group I metabotropic glutamate receptors [13].
• RESULTS: The data indicate that one single-nucleotide polymorphism, rs6871510, located in intron 1 of the Homer1 gene significantly (P=0.029) associates with cocaine dependence at the genotype level, and trends toward a significant association at the allele frequency level (chi=2.62, df=1, P=0.106, OR=1.71) [14].
• Our results suggest it is unlikely that sequence variants in the Homer genes contribute to the aetiology of schizophrenia, but the variants we identified are plausible candidates for other neuropsychiatric phenotypes [15].
• A sequence homology search using N-terminal 12 amino acid residues of the 5-kDa fragment has revealed significant homology with the Homer class of proteins implicated in signaling pathways involving metabotropic glutamate receptor and myo-inositol 1,4,5-trisphosphate receptor [16].

Anatomical context of HOMER1

• Members of the Homer family of proteins are known to form multimeric complexes capable of cross-linking plasma membrane channels (e.g. metabotropic glutamate receptor) and intracellular Ca2+ release channels (e.g. inositol trisphosphate receptor) in neurons, which potentiates Ca2+ release [17].
• We now show that long and short forms of Homer H1 (H1c and H1-EVH1) are potent activators of Ca2+ release via RyR in skeletal muscle fibers (e.g. Ca2+ sparks) and potent modulators of ryanodine binding to membranes enriched with RyR, with H1c being significantly more potent than H1-EVH1 [17].
• Because H1b is found in dendritic spines of neurons, local retention of metabotropic receptors within dendritic ER provides a potential mechanism for regulating synapse-specific expression of group I metabotropic glutamate receptors [13].
• H1b inhibits surface expression of the metabotropic glutamate receptor mGluR5 in heterologous cells, causing mGluR5 to be retained in the endoplasmic reticulum (ER) [13].
• Expression of mGluR5-GFP in clonal cell lines yielded a functional fluorescent receptor with pharmacological profiles similar to wild-type mGluR5. mGluR5-GFP coimmunoprecipitated with Homer-1c, indicating that addition of GFP to the C-terminal did not prevent Homer binding [18].

Associations of HOMER1 with chemical compounds

• Association of a polymorphism in the Homer1 gene with cocaine dependence in an African American population [14].
• In this study, we investigated the responsiveness of Homer family proteins to dopamine stimulation with the psychostimulant cocaine in rat striatal neurons both in vivo and in vitro [19].
• A modified fermentation procedure based on one described by Homer Smith in his textbook was used to eliminate glucose interference in the automated detrmination of inulin [20].
• In his hypothesis of the evolution of renal functions Homer Smith proposed that the formation of glomerular nephron and body armor had been adequate for the appearance of primitive vertebrates in fresh water and that the adaptation of homoiotherms to terrestrial life was accompanied by the appearance of the loop of Henle [21].
• The differentiation features are primarily encountered in the Homer Wright rosettes and in the reticulin-free "pale islands," or "follicles," of the desmoplastic variant [3].

Regulatory relationships of HOMER1

• In contrast, mGluR5 alone or mGluR5 coexpressed with Homer 1a successfully travels through the secretory pathway to the plasma membrane [13].
• Dendritic and axonal targeting of type 5 metabotropic glutamate receptor is regulated by homer1 proteins and neuronal excitation [22].

Other interactions of HOMER1

• TRPC1 interacts with calmodulin, caveolin-1, the InsP3 receptor, Homer, phospholipase C and several other proteins [23].
• Coexpression of wild-type mGluR5 or mGluR5-GFP with Homer 1c, but not Homer-1a, resulted in reduced receptor surface localization and the formation of intracellular clusters [18].
• CONCLUSIONS: The results of this study suggest that a polymorphism in the Homer1 gene, rs6871510, is a potential risk factor for the development of cocaine dependence in an African American population, whereas polymorphisms in the Homer2 gene are not [14].
• Anti-h beta 4 and anti-MAP2 immunostaining was consistently obtained in the Flexner-Wintersteiner rosettes, in fleurettes, in Homer Wright (neuroblastic) rosettes, and also variably among poorly differentiated tumor cells [24].
• The conventional morphological markers of differentiation in medulloblastomas such as spongioblastic cells and Homer Wright rosettes were not necessarily compatible with expression of immunohistochemical markers such as GFAP or NF [25].

Analytical, diagnostic and therapeutic context of HOMER1

• Quantitative RT-PCR analysis and the Western blotting using pan-Homer antibody revealed that mouse heart, skeletal muscle and diaphragm constitutively express high levels of the Homer proteins and their mRNAs [26].
• The binding of 4-methylumbelliferyl alpha-D-mannopyranoside (MUM) and concanavalin A, composed of intact polypeptide chains, was studied by equilibrium dialysis, difference spectroscopy, and fluorescence titration (Dean, B.R., and Homer, R.B. (1973), Biochim. Biophys. Acta. 322, 141-144), measured either at a fixed wavelength or above 350 nm [27].
• In this study we investigated the early consequences of chronic constriction injury of the sciatic nerve on Homer1 gene expression in the spinal dorsal horn [28].
• A Homer mammographic needle was placed near the lesion using CT guidance under general anesthesia [29].
• A brain tumor in the fourth ventricle of a 26-year-old woman displayed numerous Homer Wright rosettes by conventional histology, but immunostaining and electron microscopy revealed the tumor an ependymoma [30].

References