NEGR1 and FGFR2 cooperatively regulate cortical development and core behaviours related to autism disorders in mice

Szczurkowska, Joanna; Pischedda, Francesca; Pinto, Bruno; Managò, Francesca; Haas, Carola A.; Summa, Maria; Bertorelli, Rosalia; Papaleo, Francesco; Schäfer, Michael K. E.; Piccoli, Giovanni; Cancedda, Laura

doi:10.1093/brain/awy190

Cited by 53 publications

(78 citation statements)

References 140 publications

(195 reference statements)

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“…Conversely, some other models, (i.e., Pcdh19 X LacZ /Y; (Lim et al 2019)) did not show gross brain developmental abnormalities, but they did show some ASD-related behavioral phenotypes (Table 1). We found here that in rats electroporated with shRNA-Pcdh19 in the somatosensory cortex, brain developmental abnormalities were accompanied by decreased vocalisation and huddling behaviour in young pups, and poor sociability in adult animals, as already shown in animal models of ASD (Wöhr and Scattoni 2013;Scattoni, Crawley, and Ricceri 2009;Ferhat et al 2016;Szczurkowska et al 2018;Naskar et al 2019). Interestingly, also a large number (32%) of people with EIEE9 carry a diagnosis of ASD (Smith et al 2018;Clarke 2015)) with social deficits early in life that persist and may become more prominent in adulthood (Depienne et al 2011).…”

Section: Discussionsupporting

confidence: 69%

“…Furthermore, around 32% of people with EIEE9 fulfill the criteria for ASD, including sensory alterations (Smith et al 2018). Recently, we have demonstrated that downregulation in the upper layer of the somatosensory cortex of another cell-adhesion molecule (Negr1) with a similar pattern of expression as Pcdh19 and also associated to human ASD (Szczurkowska et al 2018), resulted in migration defects and core symptoms related to ASD (along with sensory alterations) in rodents (Szczurkowska et al 2018). Thus, we decided to investigate whether Pcdh19 downregulation by a short harpin RNA (shRNA) strategy (Bassani et al 2018) in the somatosensory cortex resulted in migration defects and ASD-related behaviors.…”

Section: Pcdh19 Expression Is Temporally and Spatially Regulated In Tmentioning

confidence: 99%

“…On electroporated animals, we examined coronal sections of the somatosensory cortex. We found that focal downregulation of Pcdh19 impaired neuronal migration in vivo at P9 ( Figure 2D with ASD may display an abnormal cortical laminar organization accompanied by alterations in dendritic spines (Stoner et al 2014;Reiner and Dunaevsky 2015;Varghese et al 2017;Dang et al 2018;Szczurkowska et al 2018), we investigated the number of spines in the neurons electroporated with Pcdh19 shRNA vs control littermates. In line with previous literature in layer V neurons (Hayashi et al 2017), we found that Pcdh19 deficient layer II/III neurons showed a similar number of spines per micrometer in comparison to controls (not shown, Control: 0.70 ± 0.03 spines/µm, Pcdh19 shRNA: 0.71 ± 0.03 spines/µm, Mann-Whitney test, p = 0.7).…”

Section: Pcdh19 Expression Is Temporally and Spatially Regulated In Tmentioning

confidence: 99%

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A Rat Model of a Focal Mosaic Expression of PCDH19 Replicates Human Brain Developmental Abnormalities and Behaviors

Cwetsch

Narducci

Bolla

et al. 2020

Preprint

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In BriefCwetsch et al. report a rat model of focal brain mosaicism of Pcdh19 downregulation induced by in utero electroporation aimed at mimicking the X-linked inheritance pattern of epilepticencephalopathy-early-infantile-9 (EIEE9) people. Local mosaic of Pcdh19 downregulation resulted in deficits of brain development, as well as autism-related behaviors and reduced cognitive performance. Highlights• Pcdh19-shRNA in utero electroporation of the rat brain mimics EIEE9 mosaic condition • Pcdh19 focal mosaic expression impairs migration in the cortex and hippocampus •Pcdh19-shRNA transfected rats present autism-related behaviors and cognitive deficits Summary PCDH19 gene-related epilepsy or epileptic encephalopathy, early infantile, 9 (EIEE9) is an infantile onset epilepsy syndrome characterized by psychiatric (including autistic) sensory and cognitive impairment of varying degrees. EIEE9 is caused by X-linked PCDH19 protein loss of function. Due to random X-chromosome inactivation, EIEE9-affected females present a mosaic population of healthy and Pcdh19-mutant cells. Unfortunately, no mouse models recapitulate to date both the brain histological and behavioural deficits present in people with EIEE9. Thus, the search for a proper understanding of the disease, and possible future treatment is hampered. By inducing a focal mosaicism of Pdch19 expression using in utero electroporation in rat, we found here that Pcdh19 signaling in specific brain areas is implicated in neuronal migration, as well as in core behaviors related to autism and cognitive function.

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Section: Discussionsupporting

confidence: 69%

Section: Pcdh19 Expression Is Temporally and Spatially Regulated In Tmentioning

confidence: 99%

Section: Pcdh19 Expression Is Temporally and Spatially Regulated In Tmentioning

confidence: 99%

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A Rat Model of a Focal Mosaic Expression of PCDH19 Replicates Human Brain Developmental Abnormalities and Behaviors

Cwetsch

Narducci

Bolla

et al. 2020

Preprint

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“…Direct control by Negr1 of synapse number and neurite outgrowth was also demonstrated in an in utero study [27]. When negr1 expression was silenced in mouse embryonic brain at E15.5 by in utero electroporation, dendritic length and number of neurite processes of layer II/III cortical neurons at P7 decreased significantly compared with their controls [27]. These results confirm that Negr1 deficiency prevents normal morphological development of pyramidal neurons in vivo.…”

Section: Role Of Negr1 In Neuronal Synaptogenesis and Neu-rite Outgrowthsupporting

confidence: 62%

“…Taken together, these results indicate that Negr1 is an important regulator of not only synapse number, but also of maturation of dendritic processes; moreover, its regulatory effects are dependent on the developing stages of neurons. Direct control by Negr1 of synapse number and neurite outgrowth was also demonstrated in an in utero study [27]. When negr1 expression was silenced in mouse embryonic brain at E15.5 by in utero electroporation, dendritic length and number of neurite processes of layer II/III cortical neurons at P7 decreased significantly compared with their controls [27].…”

Section: Role Of Negr1 In Neuronal Synaptogenesis and Neu-rite Outgrowthmentioning

confidence: 72%

From Bound Cells Comes a Sound Mind: The Role of Neuronal Growth Regulator 1 in Psychiatric Disorders

et al. 2020

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Cell-to-cell adhesion is important for maintenance of brain structure and function. Abnormal neuronal cell adhesion and loss of its connectivity are considered a main cause of psychiatric disorders such as major depressive disorder (MDD). Various cell adhesion molecules (CAMs) are involved in neuronal cell adhesions and thereby affect brain functions such as learning and memory, cognitive functions, and psychiatric functions. Compared with other CAMs, neuronal growth regulator 1 (Negr1) has a distinct functioning mechanism in terms of its cross-talk with cytokine receptor signaling. Negr1 is a member of the immunoglobulin LON (IgLON) family of proteins and is involved in neuronal outgrowth, dendritic arborization, and synapse formation. In humans, Negr1 is a risk gene for obesity based on a genome-wide association study. More recently, accumulating evidence supports that it also plays a critical role in psychiatric disorders. In this review, we discuss the recent findings on the role of Negr1 in MDD, focusing on its regulatory mechanism. We also provide evidence of putative involvement of Negr1 in other psychiatric disorders based on the novel behavioral phenotypes of Negr1 knockout mice.

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New developments in the biology of fibroblast growth factors

Ornitz

Itoh

2022

WIREs Mechanisms of Disease

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The fibroblast growth factor (FGF) family is composed of 18 secreted signaling proteins consisting of canonical FGFs and endocrine FGFs that activate four receptor tyrosine kinases (FGFRs 1-4) and four intracellular proteins (intracellular FGFs or iFGFs) that primarily function to regulate the activity of voltagegated sodium channels and other molecules. The canonical FGFs, endocrine FGFs, and iFGFs have been reviewed extensively by us and others. In this review, we briefly summarize past reviews and then focus on new developments in the FGF field since our last review in 2015. Some of the highlights in the past 6 years include the use of optogenetic tools, viral vectors, and inducible transgenes to experimentally modulate FGF signaling, the clinical use of small molecule FGFR inhibitors, an expanded understanding of endocrine FGF signaling, functions for FGF signaling in stem cell pluripotency and differentiation, roles for FGF signaling in tissue homeostasis and regeneration, a continuing elaboration of mechanisms of FGF signaling in development, and an expanding appreciation of roles for FGF signaling in neuropsychiatric diseases.

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NEGR1 and FGFR2 cooperatively regulate cortical development and core behaviours related to autism disorders in mice

Cited by 53 publications

References 140 publications

A Rat Model of a Focal Mosaic Expression of PCDH19 Replicates Human Brain Developmental Abnormalities and Behaviors

A Rat Model of a Focal Mosaic Expression of PCDH19 Replicates Human Brain Developmental Abnormalities and Behaviors

From Bound Cells Comes a Sound Mind: The Role of Neuronal Growth Regulator 1 in Psychiatric Disorders

New developments in the biology of fibroblast growth factors

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