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The Yin and Yang of Autosomal Recessive Primary Microcephaly Genes: Insights from Neurogenesis and Carcinogenesis

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The Yin and Yang of Autosomal Recessive Primary Microcephaly Genes: Insights from Neurogenesis and Carcinogenesis International Journal of Molecular Sciences Review The Yin and Yang of Autosomal Recessive Primary Microcephaly Genes: Insights from Neurogenesis and Carcinogenesis Xiaokun Zhou 1, Yiqiang Zhi 1, Jurui Yu 1 and Dan Xu 1,2,* 1 College of Biological Science and Engineering, Institute of Life Sciences, Fuzhou University, Fuzhou 350108, China; [email protected] (X.Z.); [email protected] (Y.Z.); [email protected] (J.Y.) 2 Fujian Key Laboratory of Molecular Neurology, Institute of Neuroscience, Fujian Medical University, Fuzhou 350005, China * Correspondence: [email protected]; Tel.: +86-17085937559 Received: 17 December 2019; Accepted: 26 February 2020; Published: 1 March 2020 Abstract: The stem cells of neurogenesis and carcinogenesis share many properties, including proliferative rate, an extensive replicative potential, the potential to generate different cell types of a given tissue, and an ability to independently migrate to a damaged area. This is also evidenced by the common molecular principles regulating key processes associated with cell division and apoptosis. Autosomal recessive primary microcephaly (MCPH) is a neurogenic mitotic disorder that is characterized by decreased brain size and mental retardation. Until now, a total of 25 genes have been identified that are known to be associated with MCPH. The inactivation (yin) of most MCPH genes leads to neurogenesis defects, while the upregulation (yang) of some MCPH genes is associated with different kinds of carcinogenesis. Here, we try to summarize the roles of MCPH genes in these two diseases and explore the underlying mechanisms, which will help us to explore new, attractive approaches to targeting tumor cells that are resistant to the current therapies. Keywords: autosomal recessive primary microcephaly; neurogenesis; carcinogenesis; centrosome; cell cycle; cell apoptosis 1. Introduction Embryonic stem cells are considered pluripotent, meaning that they are capable of differentiating into multiple cell types and maintaining the ability to self-renew to produce more of the same type of stem cells. Differentiated cells originating from stem cells make up the tissues and organs of animals and plants. Neurogenesis is the process of generating neurons by neural stem cell (NSC) proliferation, neuron migration, and differentiation. Proper neurogenesis is fundamental for normal brain development [1]. Carcinogenesis defines the initiation of a tumor, or the process of transforming normal cells into cancer cells, which is determined by some factors regulating cell growth and division [2]. Cancer stem cells (CSCs) are a subpopulation of stem-like-cell properties commonly shared with normal tissue stem cells, including extensive self-renewal ability (symmetrical and asymmetrical) and differentiation capacity [3]. CSCs exhibit characteristics of both stem cells and cancer cells [4]. Microcephaly, often described as ‘small head’, is a feature of many clinical disorders and can have environmental, maternal, or genetic etiologies. Autosomal recessive primary microcephaly (MCPH) is a rare encephalopathy caused by a dysfunction in neurodevelopment. To study the role of MCPH genes in neurogenesis and carcinogenesis, animal models and cancer cell lines or tumor tissues with MCPH gene deficiency or overexpression were established (Figure1). Many genes linked to MCPH encode Int. J. Mol. Sci. 2020, 21, 1691; doi:10.3390/ijms21051691 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 23 (MCPH) is a rare encephalopathy caused by a dysfunction in neurodevelopment. To study the role Int. J.of Mol. MCPH Sci. 2020 genes, 21, 1691 in neurogenesis and carcinogenesis, animal models and cancer cell lines or2 of tumor 20 tissues with MCPH gene deficiency or overexpression were established (Figure 1). Many genes proteinslinked involved to MCPH in encode DNArepair proteins or cellinvolved cycle in control DNA [repair5]. DNA or cell replication, cycle control DNA [5 repair,]. DNA cell replication, cycle progression,DNA repair, and thecell maintenancecycle progression, of genome and stabilitythe maintenance are fundamental of genome physiological stability processesare fundamental that needphysio to belogical tightly processes balanced that to achieveneed to be normal tightly neurogenesis balanced to achieve in the brain normal or neurogenesis other tissues in without the brain resultingor other in carcinogenesis.tissues without Bothresulting neurogenesis in carcinogenesis. and carcinogenesis Both neurogenesis have a gene and expression carcinogenesis signature have a thatgene includes expression DNA signature and histone that modifications includes DNA [6 ,and7]. Inhistone addition, modific thereations are [ overlapping6,7]. In addition, migratory there are mechanismsoverlapping between migrato neuralry mechanisms progenitor between cells (NPCs) neural and progenitor brain tumor cells stem (NPCs cells) and [8]. brain In light tumor of the stem criticalcells role[8]. ofIn MCPHlight of genesthe critical in mitosis, role of cellMCPH cycle, genes and in apoptosis mitosis, cell regulation, cycle, and it apoptosis is possible regulation, that the it inhibitionis possible of the that function the inhibition of these of genes the mayfunction specifically of these a ffgenesect the may proliferation specifically and affect survival the proliferation of tumor cellsand [9]. survival In this review, of tumor we focuscells [ on9]. novelIn this insights review, into we the focus overlapping on novel mechanisms insights into of neurogenesisthe overlapping andmechanisms carcinogenesis of byneurogenesis exploring the and role carcinogenesis of MCPH genes by in exploring brain development the role of and MCPH cancer genes occurrence. in brain Furthermore,development we tryand to cancer tap potential occurrence. strategies Furthermore, for regulating we try the to signalingtap potential of MCPH strategies genes for in regulating cancer. the signaling of MCPH genes in cancer. FigureFigure 1. The 1. The role role of MCPH of MCPH genes genes in neurogenesis in neurogenesis and and carcinogenesis. carcinogenesis. Animal Animal models model withs with MCPH MCPH genegene deficiency deficiency were were established established to studyto study the rolethe role of MCPH of MCPH genes genes in neurogenesis. in neurogenesis. MCPH MCPH gene gene overexpressionoverexpression or or knockdown knockdown was was induced induced in in cancercancer cell lines lines or or tumor tumor tissues tissues to tostudy study the therole of roleMCPH of MCPH genes genes in carcinogenesis. in carcinogenesis. At the Atsame the time, same MCPH time, gene/protein MCPH gene /expressionprotein expression was analyzed was by analyzedRNA sequencing, by RNA sequencing, real-time real-timePCR, or Western PCR, or Westernblot in carcinoma blot in carcinoma and precancerous and precancerous tissue. Cell tissue. cycle, Cellcell cycle, division, cell division, differentiation, differentiation, and apoptosis and apoptosis were examined were examined to study the to studymechanism the mechanism of neurogenesis of neurogenesisand carcinogenesis and carcinogenesis mediated mediated by MCPH by MCPH genes. genes. BrdU, BrdU, 5-bromo 5-bromo-2-2′-deoxyuridine;0-deoxyuridine; CCK CCK-8,-8, cell cellcounting counting kit-8;kit-8; EdU,EdU, 5-ethynyl-25-ethynyl-2′0-deoxyuridine;-deoxyuridine; FACS,FACS, fluorescent-activated fluorescent-activated cell cell sorting; sorting; MTT, MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; bromide; TUNEL, TUNEL, terminal terminal deoxynucleotidyl deoxynucleotidyl transferasetransferase (TdT)-mediated (TdT)-mediated dUTP dUTP nick nick end end labeling. labeling. 2. MCPH Gene Deficiency Leads to Neurogenesis Defects 2. MCPH Gene Deficiency Leads to Neurogenesis Defects MCPH patients show reduced brain size, pachygyria, and loss of the gray–white junction. Head circumference (HC) is one of the most useful indirect measurements for diagnosing microcephaly. Its clinical criterion is a HC that is three standard deviations below the mean ( 3 SD) [10]. − Int. J. Mol. Sci. 2020, 21, 1691 3 of 20 MCPH causes intellectual disability, accompanied by seizures, motor disorders, and speech and language disabilities [11]. The incidence of MCPH is about 2–12 in 10,000 live births [10]. At present, 25 genes have been identified and found to be associated with MCPH [12,13]. The cerebral cortex is the region most affected in microcephaly patients. During cortical development, MCPH genes function in several important early developmental events: NPC proliferation, differentiation into neurons, the migration of neurons to the specific position of the cortical plate, and the formation of axons and dendrites from which functional synapses are produced [14]. When any of these processes go awry because of a genetic mutation, the consequences can lead to severe neurological diseases such as MCPH. To study the function of MCPH genes, animal models with MCPH gene mutation/deficiency have been established in zebrafish, Drosophila, mice, and non-human primates (cynomolgus macaque) [12,15]. Mimicking human MCPH symptoms, the most striking phenotype of MCPH gene deficiency mice was their significantly small brain size [13]. NPC (Pax6, Sox2, and Tbr2) and neuron (Tuj1, NeuN, Tbr1, and so on) markers were applied to test the effect of MCPH gene disturbance on cortical development. Fewer cells being labeled with proliferation markers Ki67 and 5-bromo-20-deoxyuridine (BrdU) in MCPH gene-deficient
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