Deficiency of Fhl2 leads to delayed neuronal cell migration and premature astrocyte differentiation

Kim, Soung Yung; Völkl, Simon; Ludwig, Stephan; Schneider, Holm; Wixler, Viktor; Park, Jung

doi:10.1242/jcs.228940

Cited by 8 publications

(9 citation statements)

References 63 publications

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“…Wei et al reported that Ptgds accumulation in Cul4b knockout mice led to an increase in glial fibrillary acidic protein (GFAP) (Zhao et al, 2015). Furthermore, Soung demonstrated that Fhl2 deficiency resulted in an accumulation of GFAP + astrocytes, and led to the disturbed arrangement and delayed migration of neuroblasts and the development of neural stem cells (Kim et al, 2019). Based on these studies, we speculate that Ptgds‐induced GFAP accumulation may play a vital role in neuronal migration.…”

Section: Discussionmentioning

confidence: 99%

Multiple sevoflurane exposures during pregnancy inhibit neuronal migration by upregulating prostaglandin D2 synthase

Chai

Cheng

Sun

et al. 2019

Intl J of Devlp Neuroscience

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Background The second trimester is a period of neurogenesis and neuronal migration, which may be affected by exposure to anesthetics. Studies have suggested that multiple anesthetic exposures may have a significant impact on neuronal migration. Methods Pregnant C57BL/6 mice at embryonic day 14.5 were randomly divided into four groups: Con x 1, Sev x 1, Con x 2, and Sev x 2. Cortical neuronal migration in offspring mice was detected by GFP immunostaining, and the number of cells in the cortex was analyzed. Results Dual exposure to sevoflurane, not single sevoflurane exposure, caused neuronal migration deficits. Dual exposure to sevoflurane increased the expression of prostaglandin D2 synthase (Ptgds). Furthermore, Ptgds siRNA attenuated neuronal migration deficits induced by dual sevoflurane exposure. Conclusion Our study suggests that multiple sevoflurane exposures in pregnant mice may induce neuronal migration deficits in offspring mice. Additional studies comprising long‐term behavioral tests are required to confirm the effects of sevoflurane exposure during pregnancy.

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Section: Discussionmentioning

confidence: 99%

Multiple sevoflurane exposures during pregnancy inhibit neuronal migration by upregulating prostaglandin D2 synthase

Chai

Cheng

Sun

et al. 2019

Intl J of Devlp Neuroscience

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“…Furthermore, FHL2-KO mice seem to have a reduced threshold for development of several chronic diseases. It was reported that loss of the LIM-only protein FHL2 encouraged the development of corneal angiogenesis, hypertrophic cardiomyopathy (38), osteopenia (37), fibrosis (25,39,40), arthritis (30,31), psoriasis (30), and gliosis in the adult brain (41).…”

Section: Expression Of Fhl2 During Wound Healingmentioning

confidence: 99%

The role of FHL2 in wound healing and inflammation

Wixler

2019

FASEB j.

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The 4‐and‐a‐half LIM domain protein 2 (FHL2) is a multifunctional adaptor protein that can interact with cell surface receptors, cytosolic adaptor and structural proteins, kinases, and nuclear transcription factors. It is involved in numerous functional activities, including the epithelial‐mesenchymal transition, cell proliferation, apoptosis, adhesion, migration, structural stability, and gene expression. Despite this, FHL2‐knockout (KO) mice are viable and fertile with no obvious abnormalities, rather suggesting a high capacity for fine‐tuning adjustment and functional redundancy of FHL2. Indeed, challenging FHL2‐KO cells or mice provided numerous evidences for the great functional significance of FHL2. In recent years, several reviews have been published describing the high capacity of FHL2 to bind diverse proteins as well as the versatile functions of FHL2, emphasizing in particular its role in cardiovascular diseases and carcinogenesis. Here, we view the function of FHL2 from a different perspective. We summarize the published data demonstrating the impact of FHL2 on wound healing and inflammation. FHL2 seems to be involved in numerous steps of these extremely complex and multidirectional but tightly regulated tissue remodeling processes, supporting tissue repair and coordinating inflammation. Deficiency of FHL2 not only slows down ongoing wound healing but also often turns it into a chronic condition.—Wixler, V. The role of FHL2 in wound healing and inflammation. FASEB J. 33, 7799–7809 (2019). http://www.fasebj.org

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“…To evaluate the physiological role of FHL2 in adult-born DGCs, we constructed inducible overexpression and knockdown of FHL2 vectors packaged into retroviruses (Figures 3D,E). In order to avoid potential effects on cell fate determination (Kim et al, 2019), we induced expression with doxycycline from day 3, as shown in Figures 3D,E. We observed that all FHL2-RFP positive cells expressed Prox1 and DCX ( Figure 3F) thus validating our experimental approach to target adult-born neurons without affecting cell fate choice.…”

Section: Expression and Genetic Manipulation Of Fhl2 In Adult-born Dgcsmentioning

confidence: 58%

“…Although several studies have shed light on the relevance of FHL2 in terms of CNS-related pathology, including epilepsy and glioblastoma (Jamali et al, 2006;Kleiber et al, 2007;Li et al, 2008;Okamoto et al, 2013), the understanding of the regulatory role of FHL2 is yet to be fully appreciated. Recently, Kim et al (2019) reported that FHL2 is expressed by NSCs and plays a role in both fate determination of cells as well as the migratory capabilities of their progeny cells (Kim et al, 2019). To assess the physiological implication of FHL2 on the dynamic process of dendritic arborization, we report for the first time that FHL2 is expressed endogenously in adult-born hippocampal neurons and interestingly that there is a significant decline in its expression observed as these neurons mature, suggesting the participation of FHL2 during the early development of adult-born neurons.…”

Section: Discussionmentioning

confidence: 99%

“…One recent study identified an alternative action of FHL2 expressed in adult neural stem cells (NSCs) that may help explain its clinical phenotype and physiological importance in the brain. Kim et al reported that global FHL2 deletion in mice via transgenic constitutive knockout led to low self-renewal activity among NSCs, premature differentiation into astrocytes at the expense of neuronal differentiation and delayed neuroblast migration in the developing brain (Kim et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Early Dendritic Morphogenesis of Adult-Born Dentate Granule Cells Is Regulated by FHL2

Ahamad

Wang

et al. 2020

Front. Neurosci.

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Dentate granule cells (DGCs), the progeny of neural stem cells (NSCs) in the subgranular zone of the dentate gyrus (DG), must develop and functionally integrate with the mature cohort of neurons in order to maintain critical hippocampal functions throughout adulthood. Dysregulation in the continuum of DGC development can result in aberrant morphology and disrupted functional maturation, impairing neuroplasticity of the network. Yet, the molecular underpinnings of the signaling involved in adult-born DGC maturation including dendritic growth, which correlates with functional integration, remains incompletely understood. Given the high metabolic activity in the dentate gyrus (DG) required to achieve continuous neurogenesis, we investigated the potential regulatory role of a cellular metabolism-linked gene recently implicated in NSC cycling and neuroblast migration, called Four and a half LIM domain 2 (FHL2). The FHL2 protein modulates numerous pathways related to proliferation, migration, survival and cytoskeletal rearrangement in peripheral tissues, interacting with the machinery of the sphingosine-1-phosphate pathway, also known to be highly active especially in the hippocampus. Yet, the potential relevance of FHL2 to adult-born DGC development remains unknown. To elucidate the role of FHL2 in DGC development in the adult brain, we first confirmed the endogenous expression of FHL2 in NSCs and new granule cells within the DG, then engineered viral vectors for genetic manipulation experiments, investigating morphological changes in early stages of DGC development. Overexpression of FHL2 during early DGC development resulted in marked sprouting and branching of dendrites, while silencing of FHL2 increased dendritic length. Together, these findings suggest a novel role of FHL2 in adult-born DGC morphological maturation, which may open up a new line of investigation regarding the relevance of this gene in physiology and pathologies of the hippocampus such as mesial temporal lobe epilepsy (MTLE).

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Deficiency of Fhl2 leads to delayed neuronal cell migration and premature astrocyte differentiation

Cited by 8 publications

References 63 publications

Multiple sevoflurane exposures during pregnancy inhibit neuronal migration by upregulating prostaglandin D2 synthase

Multiple sevoflurane exposures during pregnancy inhibit neuronal migration by upregulating prostaglandin D2 synthase

The role of FHL2 in wound healing and inflammation

Early Dendritic Morphogenesis of Adult-Born Dentate Granule Cells Is Regulated by FHL2

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