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TAF1-gene editing alters the morphology and function of the cerebellum

Published on Jul 1, 2019in Neurobiology of Disease5.16
· DOI :10.1016/j.nbd.2019.104539
Udaiyappan Janakiraman (UA: University of Arizona), Jie Yu1
Estimated H-index: 1
(ZJNU: Zhejiang Chinese Medical University)
+ 6 AuthorsMark A. Nelson32
Estimated H-index: 32
(UA: University of Arizona)
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Abstract
Abstract TAF1/MRSX33 intellectual disability syndrome is an X-linked disorder caused by loss-of-function mutations in the TAF1 gene. How these mutations cause dysmorphology, hypotonia, intellectual and motor defects is unknown. Mouse models which have embryonically targeted TAF1 have failed, possibly due to TAF1 being essential for viability, preferentially expressed in early brain development, and intolerant of mutation. Novel animal models are valuable tools for understanding neuronal pathology. Here, we report the development and characterization of a novel animal model for TAF1 ID syndrome in which the TAF1 gene is deleted in embryonic rats using clustered regularly interspaced short palindromic repeats (CRISPR) associated protein 9 (Cas9) technology and somatic brain transgenesis mediated by lentiviral transduction. Rat pups, post-natal day 3, were subjected to intracerebroventricular (ICV) injection of either gRNA-control or gRNA-TAF1 vectors. Rats were subjected to a battery of behavioral tests followed by histopathological analyses of brains at post-natal day 14 and day 35. TAF1 -edited rats exhibited behavioral deficits at both the neonatal and juvenile stages of development. Deletion of TAF1 lead to a hypoplasia and loss of the Purkinje cells. We also observed a decreased in GFAP positive astrocytes and an increase in Iba1 positive microglia within the granular layer of the cerebellum in TAF1-edited animals. Immunostaining revealed a reduction in the expression of the CaV3.1 T-type calcium channel. Abnormal motor symptoms in TAF1-edited rats were associated with irregular cerebellar output caused by changes in the intrinsic activity of the Purkinje cells due to loss of pre-synaptic CaV3.1. This animal model provides a powerful new tool for studies of neuronal dysfunction in conditions associated with TAF1 abnormalities and should prove useful for developing therapeutic strategies to treat TAF1 ID syndrome.
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Published on Dec 1, 2018in International Journal of Developmental Neuroscience2.37
Rui Yang (CSU: Central South University), Shao Liu (CSU: Central South University)+ 3 AuthorsMimi Tang1
Estimated H-index: 1
(CSU: Central South University)
Abstract Background Polyunsaturated fatty acids (PUFAs) are normal components of growth and development and its derivatives especially n-3 PUFAs have an influence on the development and maturation of nervous system. The purpose of our present study was to investigate the effect of maternal n-3 PUFAs dietary on physical maturation and the neurobiological development of the rat offspring. Methods According to the content of n-3 PUFAs in their diets, female dams were randomly divided into three tre...
Published on Sep 28, 2018
Sarah E. Hurst1
Estimated H-index: 1
(UA: University of Arizona),
Erika Liktor-Busa1
Estimated H-index: 1
(UA: University of Arizona)
+ 16 AuthorsKeri Ramsey16
Estimated H-index: 16
(TGen: Translational Genomics Research Institute)
We investigated the genome of a 5-year-old male who presented with global developmental delay (motor, cognitive, and speech), hypotonia, possibly ataxia, and cerebellar hypoplasia of unknown origin. Whole genome sequencing (WGS) and mRNA sequencing (RNA-seq) were performed on a family having an affected proband, his unaffected parents, and maternal grandfather. To explore the molecular and functional consequences of the variant, we performed cell proliferation assays, quantitative real-time PCR ...
Published on Sep 1, 2018in Biomolecules & Therapeutics3.09
Ji-Woon Kim9
Estimated H-index: 9
(Konkuk University),
Chan Young Shin30
Estimated H-index: 30
(Konkuk University)
+ -2 AuthorsSeonmin Kim (Konkuk University)
Published on Sep 1, 2018in Behavioural Brain Research2.77
Iu. A. Sukhanova (MSU: Moscow State University), E. A. Sebentsova4
Estimated H-index: 4
(RAS: Russian Academy of Sciences)
+ 7 AuthorsN. G. Levitskaya3
Estimated H-index: 3
(MSU: Moscow State University)
Abstract Perinatal hypoxia–ischaemia is one of the leading factors that negatively influence the development of the central nervous system. Our aim was to investigate the effects of sex on the outcomes of acute neonatal hypoxia (ANH) in rat pups. Male and female Wistar rats were exposed to a hypoxic condition (8% oxygen for 120 min) at postnatal day 2 (P2). Immediately after ANH an increase in HIF1-α gene expression was observed in the rat brains, independently of sex. Brain-derived neurotrophic...
Published on Aug 1, 2018in Molecular Psychiatry11.97
Alexander J. Sandweiss3
Estimated H-index: 3
(UA: University of Arizona),
Mary I. McIntosh2
Estimated H-index: 2
(UA: University of Arizona)
+ 8 AuthorsTally M. Largent-Milnes14
Estimated H-index: 14
(UA: University of Arizona)
Development of an efficacious, non-addicting analgesic has been challenging. Discovery of novel mechanisms underlying addiction may present a solution. Here we target the neurokinin system, which is involved in both pain and addiction. Morphine exerts its rewarding actions, at least in part, by inhibiting GABAergic input onto substance P (SP) neurons in the ventral tegmental area (VTA), subsequently increasing SP release onto dopaminergic neurons. Genome editing of the neurokinin 1 receptor (NK1...
Published on Jun 15, 2018in Human Molecular Genetics4.54
Farrah El-Saafin4
Estimated H-index: 4
,
Cynthia J. Curry45
Estimated H-index: 45
(UCSF: University of California, San Francisco)
+ 12 AuthorsLuc Negroni1
Estimated H-index: 1
The human general transcription factor TFIID is composed of the TATA-binding protein (TBP) and 13 TBP-associated factors (TAFs). In eukaryotic cells, TFIID is thought to nucleate RNA polymerase II (Pol II) preinitiation complex formation on all protein coding gene promoters and thus, be crucial for Pol II transcription. In a child with intellectual disability, mild microcephaly, corpus callosum agenesis and poor growth, we identified a homozygous splice-site mutation in TAF8 (NM_138572.2: c.781-...
Published on Jun 1, 2018in Heliyon
Ramon Guirado15
Estimated H-index: 15
(University of Valencia),
Hector Carceller4
Estimated H-index: 4
(University of Valencia)
+ 2 AuthorsJuan Nacher33
Estimated H-index: 33
(University of Valencia)
Abstract The quantification of the expression of different molecules is a key question in both basic and applied sciences. While protein quantification through molecular techniques leads to the loss of spatial information and resolution, immunohistochemistry is usually associated with time-consuming image analysis and human bias. In addition, the scarce automatic software analysis is often proprietary and expensive and relies on a fixed threshold binarization. Here we describe and share a set of...
Published on Jun 1, 2018in Neuroscience3.24
Aubin Moutal11
Estimated H-index: 11
(UA: University of Arizona),
Li Sun4
Estimated H-index: 4
(JLU: Jilin University)
+ 4 AuthorsRajesh Khanna30
Estimated H-index: 30
(UA: University of Arizona)
Abstract An understudied symptom of the genetic disorder Neurofibromatosis type 1 (NF1) is chronic idiopathic pain. We used targeted editing of Nf1 in rats to provide direct evidence of a causal relationship between neurofibromin, the protein product of the Nf1 gene, and pain responses. Our study data identified a protein-interaction network with collapsin response meditator protein 2 (CRMP2) as a node and neurofibromin, syntaxin 1A, and the N-type voltage-gated calcium (CaV2.2) channel as inter...
Published on May 31, 2018
Kwan Young Lee2
Estimated H-index: 2
(UIUC: University of Illinois at Urbana–Champaign),
Yujin Jang2
Estimated H-index: 2
(Konyang University)
+ 6 AuthorsDong Kwan Kim5
Estimated H-index: 5
(Konyang University)
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