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  • Despite the highlighted brain phenotype it needs to be noted

    2018-11-05

    Despite the highlighted Cisplatin phenotype, it needs to be noted that Cdk5rap2 is ubiquitously expressed (Issa et al., 2013) and exerts functions such as maintaining centrosome function, spindle assembly and orientation, and/or cell cycle checkpoint control (Kraemer et al., 2011; Megraw et al., 2011) that are likely relevant also to other organs. So far, no progeny of affected humans has been reported, indicating a potential role of CDK5RAP2 for the germline. Moreover, a loss of the CDK5RAP2 homologous gene centrosomin (cnn) in Drosophila causes malfunctions in meiotic centrosomes and spermatid basal bodies leading to male sterility (Li et al., 1998). Cdk5rap2 mutant or Hertwig\'s anemia (an/an) mice were known solely for their hematopoietic phenotype (macrocytic, hypoproliferative anemia, leukopenia) prior to their identification as an MCPH3 model with microcephaly in 2010 (Lizarraga et al., 2010). Homozygous male Cdk5rap2 mutant mice are infertile secondary to a severe germ cell deficiency, and females cannot deliver pups (Lizarraga et al., 2010; Russell et al., 1985). Here, we show that germ cell depletion in an/an mice occurs already during early development through a mitotic delay, prolonged cell cycle, and apoptosis.
    Results and Discussion
    Experimental Procedures
    Author Contributions
    Acknowledgments The authors thank Jessica Fassbender, Susanne Kosanke, and Magdalena John for technical assistance, Jutta Schüler for advice on microscopy, and Prof. Victor Tarabykin for discussions. This work was supported by the German Research Foundation (DFG, SFB665), the Helmholtz Association by the Berlin Institute of Health (BIH, CRG1), the German Academic Exchange Service (DAAD), and the Charité Universitätsmedizin Berlin.
    Introduction Induced pluripotent stem cells (iPSCs) can be generated directly from terminally differentiated cells (Okita et al., 2007). Not only can they bypass the need for embryos but they also enable patient-specific or personalized disease modeling using iPSCs from each individual. Human iPSCs (hiPSCs) can give rise to multiple cell types, such as neurons, cardiomyocytes, and hepatocytes (Kawamura et al., 2016; Sareen et al., 2014; Tomizawa et al., 2016). Despite much research effort on directed differentiation of iPSCs in vitro and tremendous interest in mammary tissue regeneration or bioengineering, no study has reported on the induction of mammary-like cells and organoids from hiPSCs using in vitro systems. Taking a cue from our understanding of human embryonic mammary gland development (Mikkola, 2007; Propper et al., 2013), we conceptualized that the first step for in vitro induction of mammary differentiation from hiPSCs was to pattern iPSCs to non-neural ectoderm, thus enriching mammary progenitors. Formation of embryoid bodies (EBs) from iPSCs is a well-known and broadly used differentiation method, mimicking in vivo embryo development. However, this method preferentially induces neural ectoderm from iPSCs and embryonic stem cells (Zhang et al., 2013). Although neural and non-neural ectoderm cells coexist at the same embryonic stage, in vitro studies have shown that the “default” differentiation for iPSCs is the neural lineage (Schwartz et al., 2008). To convert iPSCs to cells and organoids specific to tissues originating from non-neural ectoderm, a protocol that first enriches non-neural ectoderm cells is an essential step. Although the molecular biology of early human mammary gland development is poorly understood (Javed and Lteif, 2013), studies using mouse models have revealed that the crosstalk among fibroblast growth factor (FGF)/FGF receptor, TBX3, NRG3/ERBB4, and Wnt/LEF1 signaling is critical for the specification of the mammary gland during early development (Mikkola, 2007; Propper et al., 2013; Sternlicht, 2006; Widelitz et al., 2007). In addition, BMP4 may interact with pTHrP signaling and play an essential role in early embryonic mammary gland commitment and subsequent development (Cho et al., 2006) while inhibiting hair follicle development (Hens et al., 2007). Postnatal mammary gland development is controlled by systemic and regional hormones and growth factors (Howard and Gusterson, 2000; Petersen and Polyak, 2010). In vitro studies have revealed that growth factors, such as insulin-like growth factor 1 (IGF-1), epidermal growth factor (EGF), FGF, and hepatocyte growth factor (HGF) (Gurusamy et al., 2014; Howard and Lu, 2014; Zhang et al., 2014), are critical in the growth, differentiation, and maturation of mammary epithelial cells. In addition, ectodysplasin/nuclear factor κB (NF-κB) signaling is fundamental for embryonic hormone-independent mammary ductal growth by inducing pTHrP, Wnt, and EGF signals (Lindfors et al., 2013; Voutilainen et al., 2012). Besides the aforementioned factors, extracellular matrix (ECM) also plays a key role during mammary gland development (Howard, 2012). Previous studies showed that the combination of Matrigel and Collagen I promotes branching but no protrusions into the matrix during elongation (Nguyen-Ngoc and Ewald, 2013).