The Postsynaptic Density Proteins Homer and Shank Form a Polymeric Network Structure

Hayashi, Mariko; Tang, Chunyan; Verpelli, Chiara; Narayanan, Radhakrishnan; Stearns, Marissa; Xu, Rui; Li, Huilin; Sala, Carlo; Hayashi, Yasunori

doi:10.1016/j.cell.2009.01.050

Cited by 312 publications

(255 citation statements)

References 35 publications

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“…While Homer1b/c knockdown increases both FSH␤ and LH␤ expression, knockdown of Homer1a decreases FSH␤ without changing LH␤. The differing effects of the isoforms on FSH␤ are consistent with previous work showing that Homer1a can function as a negative regulator of Homer1b/c by disrupting its tetrameric structure due to its lack of the coiled-coil region necessary for tetramerization (39). The effects of knockdown experiments are sensitive to the stoichiometry and concentration response characteristics of the mRNA targets.…”

Section: Discussionsupporting

confidence: 76%

Homer1 Alternative Splicing Is Regulated by Gonadotropin-Releasing Hormone and Modulates Gonadotropin Gene Expression

Wang

Chikina

Pinças

et al. 2014

Molecular and Cellular Biology

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Hypothalamic gonadotropin-releasing hormone (GnRH) plays a critical role in reproductive physiology by regulating folliclestimulating hormone (FSH) and luteinizing hormone (LH) gene expression in the pituitary. Analysis of gonadotrope deep-sequencing data identified a global regulation of pre-mRNA splicing by GnRH. Homer1, a gene encoding a postsynaptic density scaffolding protein, was selected for further study. Homer1 expresses a short splice form, Homer1a, and more-abundant long transcripts Homer1b/c. GnRH induced a modest increase in Homer1b/c expression and a dramatic increase in the Homer1a splice form. G protein knockdown studies suggested that the Homer1 induction, but not the regulated splicing, was G␣q/11 dependent. Phosphorylation of the splicing regulator SRp20 was found to be induced by GnRH. SRp20 depletion attenuated the GnRH-induced increase in the Homer1a-to-Homer1b/c ratio and modulated the effects of GnRH on FSH␤ and LH␤ expression. Homer1 gene knockdown resulted in increased GnRH-induced FSH␤ and LH␤ transcript levels. Furthermore, splice-form-specific reduction of Homer1b/c increased both FSH␤ and LH␤ mRNA induction, whereas reduction of Homer1a had the opposite effect on FSH␤ induction. These results indicate that the regulation of Homer1 splicing by GnRH contributes to gonadotropin gene control. Gonadotropin-releasing hormone (GnRH) plays a central role in the control of normal reproductive function by regulating the synthesis and release of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by pituitary gonadotropes. These two hormones are heterodimeric proteins composed of a common ␣ subunit and a specific ␤ subunit (1). The control of FSH␤ and LH␤ gene expression by GnRH is critical during the menstrual cycle, including ovulation, and through the various stages of reproductive life (2). Impairment of the gonadotrope response to GnRH results in reproductive disorders such as polycystic ovary syndrome (3) and provides the basis for treatment of gonadal hormone-sensitive cancers (4, 5). Therefore, understanding the molecular mechanisms involved in the response of gonadotropins to GnRH may help discover new therapeutic targets for reproductive disorders and hormone-dependent malignancies.The development of the immortalized gonadotrope cell lines ␣T3-1 and L␤T2 has facilitated the characterization of the mechanisms regulating gonadotropin subunit gene transcription (6-9). A member of the G-protein-coupled receptor family, the GnRH receptor (GnRHR) is coupled to both G␣ q/11 and G␣ s , which activate protein kinase C/mitogen-activated protein kinase (PKC/ MAPK)-and 3=-5=-cyclic AMP (cAMP)/protein kinase A-dependent pathways, respectively (for a review, see reference 10). GnRH induction of LH␤ involves PKC/MAPK signaling and the synergistic interaction of early growth response 1, steroidogenic factor 1, and paired-like homeodomain transcription factor 1 (11). Additionally, cAMP may augment LH␤ gene transcription (12, 13). GnRH induction of FSH␤ is mediated by the...

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Section: Discussionsupporting

confidence: 76%

Homer1 Alternative Splicing Is Regulated by Gonadotropin-Releasing Hormone and Modulates Gonadotropin Gene Expression

Wang

Chikina

Pinças

et al. 2014

Molecular and Cellular Biology

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“…These protein interaction domains enable SHANK proteins to interact with a multitude of postsynaptic proteins, linking SHANK proteins to ionotropic glutamate receptors via PSD-95 and PSD-95-associated protein (SAPAP) interactions 160 , intracellular Ca 2+ signaling via HOMER interactions 161 , and, actin cytoskeleton regulation via cortactin 160 , α-fodrin 162 , Rac1 163 and actin binding protein 1 (Abp1) 164 interactions, among others ( Figure 5). Cortactin, Abi-1 (Abelson interacting protein 1), and IRSp53 (insulin receptor substrate p53)…”

Section: Synaptic Scaffolding Proteins and Synaptic Vesicle Regulatormentioning

confidence: 99%

Dendritic spine actin cytoskeleton in autism spectrum disorder

Joensuu¹,

Lanoue

Hotulainen

2018

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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“…Next is a PDZ domain that binds many different molecules within the PSD, importantly including GKAP, which allows Shank to attach to PSD-95 and thereby to neuroligins [23,52] and NMDARs. The PDZ domain is followed by a proline-rich region which contains a binding site for Homer (linking Shank to the mGluR-PLC-IP 3 Ca 2þ -signalling pathway) [53,54], and a site for cortactin, a molecule that is involved in actin polymerization [52,55,56].…”

Section: The Shank Family Of Proteinsmentioning

confidence: 99%

Shank mutant mice as an animal model of autism

Yoo

Bakes

Bradley

et al. 2014

Phil. Trans. R. Soc. B

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In this review, we focus on the role of the Shank family of proteins in autism. In recent years, autism research has been flourishing. With genetic, molecular, imaging and electrophysiological studies being supported by behavioural studies using animal models, there is real hope that we may soon understand the fundamental pathology of autism. There is also genuine potential to develop a molecular-level pharmacological treatment that may be able to deal with the most severe symptoms of autism, and clinical trials are already underway. The Shank family of proteins has been strongly implicated as a contributing factor in autism in certain individuals and sits at the core of the alleged autistic pathway. Here, we analyse studies that relate Shank to autism and discuss what light this sheds on the possible causes of autism.

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The Postsynaptic Density Proteins Homer and Shank Form a Polymeric Network Structure

Cited by 312 publications

References 35 publications

Homer1 Alternative Splicing Is Regulated by Gonadotropin-Releasing Hormone and Modulates Gonadotropin Gene Expression

Homer1 Alternative Splicing Is Regulated by Gonadotropin-Releasing Hormone and Modulates Gonadotropin Gene Expression

Dendritic spine actin cytoskeleton in autism spectrum disorder

Shank mutant mice as an animal model of autism

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