C3orf70 Is Involved in Neural and Neurobehavioral Development

Abstract

Neurogenesis is the process by which undifferentiated progenitor cells develop into mature and functional neurons. Defects in neurogenesis are associated with neurodevelopmental and neuropsychiatric disorders; therefore, elucidating the molecular mechanisms underlying neurogenesis can advance our understanding of the pathophysiology of these disorders and facilitate the discovery of novel therapeutic targets. In this study, we performed a comparative transcriptomic analysis to identify common targets of the proneural transcription factors Neurog1/2 and Ascl1 during neurogenesis of human and mouse stem cells. We successfully identified C3orf70 as a novel common target gene of Neurog1/2 and Ascl1 during neurogenesis. Using in situ hybridization, we demonstrated that c3orf70a and c3orf70b, two orthologs of C3orf70, were expressed in the midbrain and hindbrain of zebrafish larvae. We generated c3orf70 knockout zebrafish using CRISPR/Cas9 technology and demonstrated that loss of c3orf70 resulted in significantly decreased expression of the mature neuron markers elavl3 and eno2. We also found that expression of irx3b, a zebrafish ortholog of IRX3 and a midbrain/hindbrain marker, was significantly reduced in c3orf70 knockout zebrafish. Finally, we demonstrated that neurobehaviors related to circadian rhythm and altered light–dark conditions were significantly impaired in c3orf70 knockout zebrafish. These results suggest that C3orf70 is involved in neural and neurobehavioral development and that defects in C3orf70 may be associated with midbrain/hindbrain-related neurodevelopmental and neuropsychiatric disorders.

An Epithelial-Mesenchymal Transition (EMT) Preoperative Nomogram for Prediction of Lymph Node Metastasis in Bladder Cancer (BLCA)

“…Moreover, multivariable logistic regression analysis demonstrated that only mutation of C3ort70 remained as a significant variable in the predictive model. Recently, C3orf70 was reported to be involved in neural and neurobehavioral development [ 65 ]. Ward et al establish a 23-gene panel containing C3orf70 with utility for noninvasive diagnosis and risk stratification of BLCA [ 66 ].…”

Zebrafish Is a Powerful Tool for Precision Medicine Approaches to Neurological Disorders

“…Only a limited number of studies to date have used novel targeted-mutagenesis techniques such as CRISPR/Cas9 to generate target discovery studies in the neuroscience field. However, it is expected that a growing number of studies will be reported soon ( Rubbini et al, 2020 ) as shown by the example of target identification in a C3orf70 knockout zebrafish mutants with impaired circadian rhythm and altered light-dark neurobehaviors ( Ashikawa et al, 2019 ) in which the C3orf70 gene was reported to be a shared target of Neurog1/2 and Asc11 . As a result, C3orf70 mutations may be linked to neurodevelopmental and neuropsychiatric diseases in these brain locations and could be exploited as a therapeutic target ( Ashikawa et al, 2019 ).…”

“…However, it is expected that a growing number of studies will be reported soon ( Rubbini et al, 2020 ) as shown by the example of target identification in a C3orf70 knockout zebrafish mutants with impaired circadian rhythm and altered light-dark neurobehaviors ( Ashikawa et al, 2019 ) in which the C3orf70 gene was reported to be a shared target of Neurog1/2 and Asc11 . As a result, C3orf70 mutations may be linked to neurodevelopmental and neuropsychiatric diseases in these brain locations and could be exploited as a therapeutic target ( Ashikawa et al, 2019 ). Target identification can also arise from exploratory transcriptomics investigation on a genetic zebrafish model for a particular disease.…”

CRISPR Meets Zebrafish: Accelerating the Discovery of New Therapeutic Targets

“…Thus, defects in C3orf70 may be associated with neurodevelopmental and neuropsychiatric disorders related to these brain areas, and therefore might be used as therapeutic targets. 42 A more recent publication shows the combined effort led by Harvard University and Novartis to use zebrafish for tackling psychiatric disorders. Harvard’s Fishman Lab has generated mutants for 90 genes associated, through GWAS studies, with autism, schizophrenia, and other disorders in humans.…”