Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice

Wang, I-Ting Judy; Allen, Martin G.; Goffin, Darren; Zhu, Xinjian; Fairless, Andrew H.; Brodkin, Edward S.; Siegel, Steven J.; Marsh, Eric D.; Blendy, Julie A.; Zhou, Zhaolan

doi:10.1073/pnas.1216988110

Cited by 181 publications

(286 citation statements)

References 54 publications

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“…Having a screening approach in mind, we tested well-characterized S/T phosphorylation motif antibodies, which detect all phosphorylated PKA/PKC substrates in brain lysates. 33 There is a global phosphorylation increase in the Injury compared with the Sham group (Figure 2a), which is in line with the notion that inflammatory and/or ischemic insults activate PKA/PKC signaling. [34][35][36] Importantly, we detected a further increase in phosphorylation in the Injury+sPIF compared with the Injury group, suggesting possible modulation of PKA/PKC signaling by sPIF.…”

supporting

confidence: 85%

PreImplantation Factor bolsters neuroprotection via modulating Protein Kinase A and Protein Kinase C signaling

et al. 2015

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A synthetic peptide (sPIF) analogous to the mammalian embryo-derived PreImplantation Factor (PIF) enables neuroprotection in rodent models of experimental autoimmune encephalomyelitis and perinatal brain injury. The protective effects have been attributed, in part, to sPIF's ability to inhibit the biogenesis of microRNA let-7, which is released from injured cells during central nervous system (CNS) damage and induces neuronal death. Here, we uncover another novel mechanism of sPIF-mediated neuroprotection. Using a clinically relevant rat newborn brain injury model, we demonstrate that sPIF, when subcutaneously administrated, is able to reduce cell death, reverse neuronal loss and restore proper cortical architecture. We show, both in vivo and in vitro, that sPIF activates cyclic AMP dependent protein kinase (PKA) and calcium-dependent protein kinase (PKC) signaling, leading to increased phosphorylation of major neuroprotective substrates GAP-43, BAD and CREB. Phosphorylated CREB in turn facilitates expression of Gap43, Bdnf and Bcl2 known to have important roles in regulating neuronal growth, survival and remodeling. As is the case in sPIF-mediated let-7 repression, we provide evidence that sPIF-mediated PKA/PKC activation is dependent on TLR4 expression. Thus, we propose that sPIF imparts neuroprotection via multiple mechanisms at multiple levels downstream of TLR4. Given the recent FDA fast-track approval of sPIF for clinical trials, its potential clinical application for treating other CNS diseases can be envisioned.

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supporting

confidence: 85%

PreImplantation Factor bolsters neuroprotection via modulating Protein Kinase A and Protein Kinase C signaling

et al. 2015

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“…To identify the minimal binding motif, we generated a series of N-terminal deletion mutants of PSD-95 with GFP fused to their C termini and tested their interaction with CDKL5. We observed that PSD-95 (amino acids 1-21), PSD-95 (amino acids [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20], and PSD-95 (amino acids [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] bound to CDKL5 at comparable levels (Fig. 2B).…”

Section: Psd-95mentioning

confidence: 79%

“…Loss-of-function studies using RNA interference (RNAi) revealed that CDKL5 is required for neurite growth and excitatory synapse stability (5,7). Deficiency of CDKL5 in mice leads to autistic-like phenotypes, indicating a causal role for CDKL5 loss of function in disease (8).…”

mentioning

confidence: 99%

Palmitoylation-dependent CDKL5–PSD-95 interaction regulates synaptic targeting of CDKL5 and dendritic spine development

Yingguo¹,

Li²,

Wang³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The X-linked gene cyclin-dependent kinase-like 5 (CDKL5) is mutated in severe neurodevelopmental disorders, including some forms of atypical Rett syndrome, but the function and regulation of CDKL5 protein in neurons remain to be elucidated. Here, we show that CDKL5 binds to the scaffolding protein postsynaptic density (PSD)-95, and that this binding promotes the targeting of CDKL5 to excitatory synapses. Interestingly, this binding is not constitutive, but governed by palmitate cycling on PSD-95. Furthermore, pathogenic mutations that truncate the C-terminal tail of CDKL5 diminish its binding to PSD-95 and synaptic accumulation. Importantly, downregulation of CDKL5 by RNA interference (RNAi) or interference with the CDKL5-PSD-95 interaction inhibits dendritic spine formation and growth. These results demonstrate a critical role of the palmitoylation-dependent CDKL5-PSD-95 interaction in localizing CDKL5 to synapses for normal spine development and suggest that disruption of this interaction by pathogenic mutations may be implicated in the pathogenesis of CDKL5-related disorders.M utations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) have been identified in patients with severe neurodevelopmental disorders, including an early-onset variant of Rett syndrome (1, 2). The predicted protein encoded by CDKL5 gene belongs to the CDKL family that comprises five members, CDKL1 to CDKL5 (3). The expression of CDKL5 is enriched in human and rat brain (4, 5). In murine, CDKL5 is expressed at low levels in embryonic stages and its expression is markedly upregulated during postnatal development (5, 6). Loss-of-function studies using RNA interference (RNAi) revealed that CDKL5 is required for neurite growth and excitatory synapse stability (5, 7). Deficiency of CDKL5 in mice leads to autistic-like phenotypes, indicating a causal role for CDKL5 loss of function in disease (8).Several interacting partners of CDKL5 have been reported, including the Rett syndrome-related protein methyl-CpG binding protein 2 (MeCP2) (9), the DNA methyltransferase Dnmt1 (10), and netrin-G1 ligand (NGL-1) (7). All of the three proteins are potential substrates for CDKL5, at least as demonstrated in vitro, suggesting that CDKL5 elicits its function by phosphorylating target proteins. Although the kinase activity of CDKL5 is required for its function and is impaired by some mutations identified in patients (7, 11), the regulation of CDKL5 seems to be equally important in the pathogenesis of disease, which is suggested by a number of pathogenic mutations identified within its C-terminal region (12). Therefore, further identification of CDKL5-interacting proteins may uncover the regulatory mechanisms for CDKL5, which is an important step toward the understanding of the causes of CDKL5-related disorders.The multidomain protein postsynaptic density (PSD)-95 is a major scaffold in the postsynaptic density (PSD) (13), and has been extensively investigated during the past decade. These studies have established the essential role of PSD-95 in syn...

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“…CDKL5 knockdown in cultured hippocampal neurons results in aberrant spine morphology (Chen et al, 2010) and unstable dendritic spines . Intriguingly, the analysis of novel mouse models carrying Cdkl5 deletion showed alterations in sensory evoked potentials both in the auditory and the visual cortices (Wang et al, 2012, Amendola et al, 2014).In conclusion, Foxg1haploinsufficiency causes a severe impairment in visual function that is likely due to altered cortical mechanisms. This should be taken into account when Foxg1 +/Cre mice are used in behavioral experiments and when visual function is evaluated in patients carrying FOXG1…”

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confidence: 97%

Visual impairment in FOXG1-mutated individuals and mice

et al. 2016

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The Forkead Box G1 (FOXG1) gene encodes for a DNA−binding transcription factor, essential for the development of the telencephalon in mammalian forebrain. Mutations in FOXG1 have been reported to be involved in the onset of Rett Syndrome, for which sequence alterations of MECP2 and CDKL5 are known. While visual alterations are not classical hallmarks of Rett syndrome, an increasing body of evidence shows visual impairment in patients and in MeCP2 and CDKL5 animal models. Herein we focused on the functional role of FOXG1 in the visual system of animal models (Foxg1+/Cre mice) and of a cohort of patients carrying FOXG1 mutations or deletions. Visual physiology of Foxg1+/Cre mice was assessed by visually evoked potentials, which revealed a significant reduction in response amplitude and visual acuity with respect to wild-type littermates. Morphological investigation showed abnormalities in the organization of excitatory/inhibitory circuits in the visual cortex. No alterations were observed in retinal structure. By examining a cohort of FOXG1-mutated patients by means of a panel of neuro-ophthalmological evaluations, we found that all of them exhibited visual alterations compatible with high level visual dysfunctions. In conclusion our data show that Foxg1 haploinsufficiency results in an impairment of mouse and patient visual function. Response to Reviewers: Pisa February 27th 2016Dear Editor, We would like to thank the referees for the thoughtful critiques on our manuscript and for the opportunity to revise our work. Please find enclosed a revised version of our manuscript (NSC-15-1232) entitled "Visual impairment in FOXG1-mutated patients and mice" by Boggio et al. As requested, we performed additional experiments on retina and visual cortex in order to more quantitavely prove the structure specific alterations and strengthen our conclusions. We included below a detailed response to the reviewer comments (in italics). References have been updated and added as suggested by referees. Sincerely, Tommaso PizzorussoReviewer #1:Major concerns 1.The description of the morphology of the five classes of retinal neurons would benefit from a quantitative approach amenable to statistical comparisons, similar to that performed for cortical GABAergic neurons in Fig. 4.We performed the requested quantitative analysis that is now shown in fig. 4. The analysis was focussed on cells in the ganglion cell layer because this layer is known to be affected in Foxg1 null mice. No significant change in the overall number of cells, and in ganglion cells identified using the RBPMS cell type-specific antibody, was present in Foxg1 heterozygous mice 2.There are no explicit statements regarding blinding of investigators to mouse genotypes during data acquisition and analyses, the use of Power Analysis to determine sample sizes, and predetermined criteria to exclude data sets. These are all critical issues that need to be performed and explicitly reported as recommended (Landis et al. Nature 2012).We included in the methods the fol...

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Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice

Cited by 181 publications

References 54 publications

PreImplantation Factor bolsters neuroprotection via modulating Protein Kinase A and Protein Kinase C signaling

PreImplantation Factor bolsters neuroprotection via modulating Protein Kinase A and Protein Kinase C signaling

Palmitoylation-dependent CDKL5–PSD-95 interaction regulates synaptic targeting of CDKL5 and dendritic spine development

Visual impairment in FOXG1-mutated individuals and mice

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