The X-Linked Intellectual Disability Gene Zdhhc9 Is Essential for Dendrite Outgrowth and Inhibitory Synapse Formation

Shimell, Jordan J.; Shah, Bhavin S.; Cain, Stuart M.; Thouta, Samrat; Kuhlmann, Naila; Tatarnikov, Igor; Jovellar, D. Blair; Brigidi, G. Stefano; Kass, Jennifer; Milnerwood, Austen J.; Snutch, Terrance P.; Bamji, Shernaz X.

doi:10.1016/j.celrep.2019.10.065

Cited by 46 publications

(98 citation statements)

References 131 publications

(136 reference statements)

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“…Of these, five—including MYRF, Otud7b, Zdhhc9, Efnb3 , and Nudt4 —were indeed found to be upregulated in miR‐145‐5p knockdown OPCs (Figure 6c). Aside from MYRF, none of the additionally identified targets have known roles in OL differentiation or myelin formation—though Otud7b, Zdhhc9 , and Efnb3 have been characterized to some degree in neurons (Cui et al, 2018; Henderson et al, 2019; Shimell et al, 2019). This certainly does not preclude them from having undiscovered roles in OLs; however, expression of all four were normalized concurrent with MYRF knockdown in anti‐145 OPCs.…”

Section: Discussionmentioning

confidence: 99%

MiRNA‐145‐5p prevents differentiation of oligodendrocyte progenitor cells by regulating expression of myelin gene regulatory factor

Kornfeld

Cummings

Fathi

et al. 2020

Journal Cellular Physiology

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The roles of specific microRNAs (miRNA) in oligodendrocyte (OL) differentiation have been studied in depth. However, miRNAs in OL precursors and oligodendrocyte progenitor cells (OPCs) have been less extensively investigated. MiR-145-5p is highly expressed in OPCs relative to differentiating OLs, suggesting this miRNA may serve a function specifically in OPCs. Knockdown of miR-145-5p in primary OPCs led to spontaneous differentiation, as evidenced by an increased proportion of MAG + cells, increased cell ramification, and upregulation of multiple myelin genes including MYRF, TPPP, and MAG, and OL cell cycle exit marker Cdkn1c. Supporting this transition to a differentiating state, proliferation was reduced in miR-145-5p knockdown OPCs. Further, knockdown of miR-145-5p in differentiating OLs showed enhanced differentiation, with increased branching, myelin membrane production, and myelin gene expression. We identified several OL-specific genes targeted by miR-145-5p that exhibited upregulation with miR-145-5p knockdown, including myelin gene regulatory factor (MYRF), that could be regulating the prodifferentiation phenotype in both miR-145 knockdown OPCs and OLs. Indeed, spontaneous differentiation with knockdown of miR-145-5p was fully rescued by concurrent knockdown of MYRF. However, proliferation rate was only partially rescued with MYRF knockdown, and overexpression of miR-145-5p in OPCs increased proliferation rate without affecting expression of already lowly expressed differentiation genes. Taken together, these data suggest that in OPCs miR-145-5p both prevents differentiation at least in part by preventing expression of MYRF and promotes proliferation via as-yet-unidentified mechanisms. These findings clarify the need for differential regulation of miR-145-5p between OPCs and OLs and may have further implications in demyelinating diseases such as multiple sclerosis where miR-145-5p is dysregulated.

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Section: Discussionmentioning

confidence: 99%

MiRNA‐145‐5p prevents differentiation of oligodendrocyte progenitor cells by regulating expression of myelin gene regulatory factor

Kornfeld

Cummings

Fathi

et al. 2020

Journal Cellular Physiology

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“…Loss-of-function variants in the Golgi-localized ZDHHC9 are linked to X-linked intellectual disability (XLID) (Han et al, 2017;Masurel-Paulet et al, 2014;Mitchell et al, 2014;Raymond et al, 2007;Tzschach et al, 2015), sometimes with an increased incidence of epilepsy (Baker et al, 2015). zDHHC9 regulates of dendritic growth and inhibitory synapse formation through the palmitoylation of the two GTPases, Ras and TC10, with significant implications for maintaining excitatory/inhibitory (E/I) balance in the brain (Shimell et al, 2019). Zdhhc9-knockout mice have altered E/I balance and exhibit seizure-like activity, which could contribute to XLID etiology.…”

Section: Pat Localization In Health and Diseasementioning

confidence: 99%

“…Zdhhc9-knockout mice have altered E/I balance and exhibit seizure-like activity, which could contribute to XLID etiology. (Shimell et al, 2019). Genome-wide association studies have found deletions in the region of chromosome 11 that encodes ZDHHC5 in patients with bipolar disorder and schizophrenia (Fallin et al, 2004; Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014).…”

Section: Pat Localization In Health and Diseasementioning

confidence: 99%

Spatial organization of palmitoyl acyl transferases governs substrate localization and function

Philippe

Jenkins

2019

Molecular Membrane Biology

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Protein palmitoylation is a critical posttranslational modification that regulates protein trafficking, localization, stability, sorting and function. In mammals, addition of this lipid modification onto proteins is mediated by a family of 23 palmitoyl acyl transferases (PATs). PATs often palmitoylate substrates in a promiscuous manner, precluding our understanding of how these enzymes achieve specificity for their substrates. Despite generous efforts to identify consensus motifs defining PAT-substrate specificity, it remains to be determined whether additional factors beyond interaction motifs, such as local palmitoylation, participate in PAT-substrate selection. In this review, we emphasize the role of local palmitoylation, in which substrates are palmitoylated and trapped in the same subcellular compartments as their PATs, as a mechanism of enzymesubstrate specificity. We focus here on non-Golgi-localized PATs, as physical proximity to their substrates enables them to engage in local palmitoylation, compared to Golgi PATs, which often direct trafficking of their substrates elsewhere. PAT subcellular localization may be an under-recognized, yet important determinant of PAT-substrate specificity that may work in conjunction or completely independently of interaction motifs. We also discuss some current hypotheses about protein motifs that contribute to localization of non-Golgi-localized PATs, important for the downstream targeting of their substrates.

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“…To determine whether Zdhhc5 is involved in dendritic arborization and/or the formation of excitatory and inhibitory synapses, hippocampal neurons were transfected with eGFP plus the indicated constructs and immunostained for PSD-95 and gephyrin (faithful markers of excitatory and inhibitory synapses, respectively (Brigidi et al, 2015;Shah et al, 2019;Shimell et al, 2019); masking shown in Supplementary Figure 1A, B). While Zdhhc5 knockdown did not impact dendritic length ( Figure 1A), complexity ( Figure 1B Figure 1B for the creation of masks to quantify synaptic marker density).…”

Section: Zdhhc5 Promotes Excitatory Synapse Formation and Regulates Smentioning

confidence: 99%

“…Biotinylation experiments were performed as previously described (Shimell et al, 2019). Briefly, neurons in 10cm dishes were nucleofected with indicated constructs and experiments were carried out at 13 DIV.…”

Section: Biotinylation Assaymentioning

confidence: 99%

Regulation of Hippocampal Excitatory Synapses by the Zdhhc5 Palmitoyl Acyl Transferase

Shimell

Globa

Sepers

et al. 2020

Preprint

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Palmitoylation is the most common post-translational lipid modification in the brain; however, the role of palmitoylation and palmitoylating enzymes in the nervous system remains elusive. One of these enzymes, Zdhhc5, has previously been shown to regulate synapse plasticity. Here, we report that Zdhhc5 is also essential for the formation of excitatory, but not inhibitory synapses both in vitro and in vivo. We demonstrate in vitro that this is dependent on Zdhhc5’s enzymatic activity, its localization at the plasma membrane, and its C-terminal domain which has been shown to be truncated in a patient with schizophrenia. Loss of Zdhhc5 in mice results in a decrease in the density of excitatory hippocampal synapses accompanied by alterations in membrane capacitance and synaptic currents, consistent with an overall decrease in spine number and silent synapses. These findings reveal an important role for Zdhhc5 in the formation and/or maintenance of excitatory synapses.

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The X-Linked Intellectual Disability Gene Zdhhc9 Is Essential for Dendrite Outgrowth and Inhibitory Synapse Formation

Cited by 46 publications

References 131 publications

MiRNA‐145‐5p prevents differentiation of oligodendrocyte progenitor cells by regulating expression of myelin gene regulatory factor

MiRNA‐145‐5p prevents differentiation of oligodendrocyte progenitor cells by regulating expression of myelin gene regulatory factor

Spatial organization of palmitoyl acyl transferases governs substrate localization and function

Regulation of Hippocampal Excitatory Synapses by the Zdhhc5 Palmitoyl Acyl Transferase

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