Clinical Phenotypes Associated to Engrailed 2 Gene Alterations in a Series of Neuropediatric Patients

Carratalá-Marco, Francisco; Andreo-Lillo, P.; Martinez-Morga, Marta; Escamez-Martínez, Teresa; Botella-López, Arancha; Bueno, Carlos

doi:10.3389/fnana.2018.00061

Cited by 12 publications

(8 citation statements)

References 58 publications

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“…Subsequently, it was found that EN signaling was also required for proper targeting of cerebellar mossy fiber afferents (Sillitoe et al, 2010). Building on the original EN association studies (Gharani et al, 2004), a recent report has confirmed the importance of EN signaling in the manifestations of ASD, while also finding that the clinical manifestation of the disease was not tightly associated with the particular polymorphism expressed in a given affected patient (Carratala-Marco et al, 2018). This may not be surprising given the complexity of somatotopy in cerebellar function (Apps and Hawkes, 2009) as well as the finding that multiple molecular mechanisms, not just EN, are required for cerebellar patterning in both the AP and ML axes (Sillitoe and Joyner, 2007;White and Sillitoe, 2013).…”

Section: Mouse Models Of Cerebellar Cognitive Disordersmentioning

confidence: 96%

Functional Outcomes of Cerebellar Malformations

Gill

Sillitoe

2019

Front. Cell. Neurosci.

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The cerebellum is well-established as a primary center for controlling sensorimotor functions. However, recent experiments have demonstrated additional roles for the cerebellum in higher-order cognitive functions such as language, emotion, reward, social behavior, and working memory. Based on the diversity of behaviors that it can influence, it is therefore not surprising that cerebellar dysfunction is linked to motor diseases such as ataxia, dystonia, tremor, and Parkinson’s disease as well to non-motor disorders including autism spectrum disorders (ASD), schizophrenia, depression, and anxiety. Regardless of the condition, there is a growing consensus that developmental disturbances of the cerebellum may be a central culprit in triggering a number of distinct pathophysiological processes. Here, we consider how cerebellar malformations and neuronal circuit wiring impact brain function and behavior during development. We use the cerebellum as a model to discuss the expanding view that local integrated brain circuits function within the context of distributed global networks to communicate the computations that drive complex behavior. We highlight growing concerns that neurological and neuropsychiatric diseases with severe behavioral outcomes originate from developmental insults to the cerebellum.

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Section: Mouse Models Of Cerebellar Cognitive Disordersmentioning

confidence: 96%

Functional Outcomes of Cerebellar Malformations

Gill

Sillitoe

2019

Front. Cell. Neurosci.

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“…A recent study [73] reported that En1 shows a transcriptional dependency in triple negative breast cancer associated with brain metastasis. Carratala-Marco et al [74] found that EN plays an important role in the regionalization of the neural tube and EN’s distribution regulates cerebellum and midbrain morphogenesis, as well as retinotectal synaptogenesis.…”

Section: Resultsmentioning

confidence: 99%

Joint dimension reduction and clustering analysis for single-cell RNA-seq and spatial transcriptomics data

Liu

Liao

Zhou

et al. 2021

Preprint

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Dimension reduction and (spatial) clustering are two key steps for the analysis of both single-cell RNA-sequencing (scRNA-seq) and spatial transcriptomics data collected from different platforms. Most existing methods perform dimension reduction and (spatial) clustering sequentially, treating them as two consecutive stages in tandem analysis. However, the low-dimensional embeddings estimated in the dimension reduction step may not necessarily be relevant to the class labels inferred in the clustering step and thus may impair the performance of the clustering and other downstream analysis. Here, we develop a computation method, DR-SC, to perform both dimension reduction and (spatial) clustering jointly in a unified framework. Joint analysis in DR-SC ensures accurate (spatial) clustering results and effective extraction of biologically informative low-dimensional features. Importantly, DR-SC is not only applicable for cell type clustering in scRNA-seq studies but also applicable for spatial clustering in spatial transcriptimics that characterizes the spatial organization of the tissue by segregating it into multiple tissue structures. For spatial transcriptoimcs analysis, DR-SC relies on an underlying latent hidden Markov random field model to encourage the spatial smoothness of the detected spatial cluster boundaries. We also develop an efficient expectation-maximization algorithm based on an iterative conditional mode. DR-SC is not only scalable to large sample sizes, but is also capable of optimizing the spatial smoothness parameter in a data-driven manner. Comprehensive simulations show that DR-SC outperforms existing clustering methods such as Seurat and spatial clustering methods such as BayesSpace and SpaGCN and extracts more biologically relevant features compared to the conventional dimension reduction methods such as PCA and scVI. Using 16 benchmark scRNA-seq datasets, we demonstrate that the low-dimensional embeddings and class labels estimated from DR-SC lead to improved trajectory inference. In addition, analyzing three published scRNA-seq and spatial transcriptomics data in three platforms, we show DR-SC can improve both the spatial and non-spatial clustering performance, resolving a low-dimensional representation with improved visualization, and facilitate the downstream analysis such as trajectory inference.

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“…Two intronic EN2 polymorphisms have been genetically associated with ASD and have been shown in independent cohorts and populations to be overtransmitted to autistic offspring from heterozygous parents (reviewed in Brune et al, 2008;Choi et al, 2011;Kuan et al, 2015;Sen et al, 2010;Wang et al, 2008). Additionally, rare mutations in EN2 have been reported in ASD patients (Carratala-Marco et al, 2018;Hnoonual et al, 2016), and dysregulation of EN2 expression has been observed in two independent studies of postmortem cerebellar tissue in ASD (Choi et al, 2014;James et al, 2013). Thus, autism-related behaviors in the En2-KO such as learning deficits and depressive phenotypes can be influenced by abnormal neurogenesis and reduced numbers of neurons in the hippocampus (Genestine et al, 2015) and directly regulated by hippocampal expression of En2.…”

Section: En2 and Neurodevelopmental Disordersmentioning

confidence: 99%

Engrailed‐2 is a cell autonomous regulator of neurogenesis in cultured hippocampal neural stem cells

Durens

Soliman

Millonig

et al. 2021

Developmental Neurobiology

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Abnormalities in genes that regulate early brain development are known risk factors for neurodevelopmental disorders. Engrailed-2 (En2) is a homeodomain transcription factor with established roles in cerebellar patterning. En2 is highly expressed in the developing mid-hindbrain region, and En2 knockout (KO) mice exhibit major deficits in mid-hindbrain structures. However, En2 is also expressed in forebrain regions including the hippocampus, but its function is unknown. Previous studies have shown that the hippocampus of En2-KO mice exhibits reductions in its volume and cell numbers due to aberrant neurogenesis. Aberrant neurogenesis is due, in part, to noncell autonomous effects, specifically, reductions of innervating norepinephrine fibers from the locus coeruleus. In this study, we investigate possible cell autonomous roles of En2 in hippocampal neurogenesis. We examine proliferation, survival, and differentiation using cultures of hippocampal neurospheres of P7 wild-type (WT) and En2-KO hippocampal neural progenitor cells (NPCs). At 7 days, En2-KO neurospheres were larger on average than WT spheres and exhibited 2.5fold greater proliferation and 2-fold increase in apoptotic cells, similar to in vivo KO phenotype. Further, En2-KO cultures exhibited 40% less cells with neurite projections, suggesting decreased differentiation. Lastly, reestablishing En2 expression in En2-KO NPCs rescued excess proliferation. These results indicate that En2 functions in hippocampal NPCs by inhibiting proliferation and promoting survival and differentiation in a cell autonomous manner. More broadly, this study suggests that En2 impacts brain structure and function in diverse regions outside of the mid-hindbrain. K E Y W O R D Sanimal models, engrailed-2, hippocampal neurogenesis, neural progenitor/stem cell cultures, neurodevelopmental disorders Significance statementAlthough En2 function in mid-hindbrain development is widely characterized, consistent expression in forebrain regions has been reported, but its function(s) remains unknown. In this study, we found that relatively low levels of En2 in the hippocampus contribute to hippocampal neurogenesis in a cell-autonomous manner, by influencing proliferation, apoptosis, and differentiation of hippocampal NPCs. In conjunction with our previous results, these data indicate that En2 regulates hippocampal neurogenesis in both a cell autonomous and non-cell autonomous manner. In turn, | 725

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Clinical Phenotypes Associated to Engrailed 2 Gene Alterations in a Series of Neuropediatric Patients

Cited by 12 publications

References 58 publications

Functional Outcomes of Cerebellar Malformations

Functional Outcomes of Cerebellar Malformations

Joint dimension reduction and clustering analysis for single-cell RNA-seq and spatial transcriptomics data

Engrailed‐2 is a cell autonomous regulator of neurogenesis in cultured hippocampal neural stem cells

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