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  • br Acknowledgments The authors acknowledge funding from the


    Acknowledgments The authors acknowledge funding from the National Key Research and Development Program of China (2016YFA0502900) and the National Science Foundation of China (31570188).
    Compartment Size Regulation Regulation of compartment size is one of the most fundamental issues in biology and medicine 1, 2. During embryogenesis, cells become committed to specific cell fates, which are subsequently followed by expansion phases in which progenitor cells divide. When the final compartment size is reached, cells exit the cell cycle and further differentiation occurs [3]. Differences in compartment size represent an important driving force in evolution and in taxonomic descriptions of species, whereas the understanding of the forces that regulate compartment size defines one of the most important outstanding questions in embryology. Furthermore, aberrant compartment size regulation is implicated in many pathologies (most dramatically, perhaps, in cancer) and, thus, knowledge of the molecular factors that determine and maintain proliferation in progenitors is a significant focus across research fields (Figure 1). Hence, understanding the molecular mechanisms governing compartment size in vertebrates is highly relevant. Nevertheless, the components in this process remain largely obscure [4]. In this review, we concentrate on the role of the Ankyrin repeat (see Glossary) and SOCS box-containing protein (Asb) family in mammalian compartment size control. In 2006, in an effort to discover the genetic participants involved in compartment size regulation, the Hubrecht Laboratory in Utrecht performed a screen in Danio rerio (zebrafish) to identify gene products the presence of which is essential for maintaining the proliferation of neural progenitors during embryogenesis [5]. To this end, zebrafish embryos were either left untreated or pulse-treated with all-trans retinoic Imeglimin hydrochloride (RA). RA treatment is well established to end compartment expansion and result in premature terminal differentiation. Thus, it was used for a differential display employing the transcripts from the untreated embryos as driver cDNA and the transcripts from the retinoic acid (RA)-treated embryos as tester cDNA. The resulting differential fragments were tested using whole-mount in situ hybridization at different developmental stages and one fragment was singled out based on its restricted spatiotemporal expression pattern during late gastrulation and early somitogenesis. The gene isolated was homologous to mammalian Asb11. Morpholino-mediated loss-of-function by knockdown of in zebrafish abrogated the expansion phase in the central nervous system (CNS) and induced premature neuronal differentiation followed by a reduced size of the definitive neuronal compartment and a small brain. Conversely, misexpression of d-asb11 mRNA in zebrafish diminished or entirely abolished terminally differentiated primary neurons, and increased the size of the neural compartment, producing prominent brain hypertrophy (Figure 2). Thus, d-asb11 emerged as an important novel regulator of the size of the neuronal progenitor cell compartment [5]. Subsequent studies showed that ASB11 has been subject to positive selection during evolution from a chimpanzee-like ancestor to humans [6]. This is the more striking in view of the otherwise high evolutionary conservation of the Asb11 gene between different Chordata [in nonchordates, which do not have a vertebral column anlage and neural tube, Asb proteins are not common, and Asb11 remains the only Asb gene identified in Urochordata, such as the ascidian Ciona intestinalis (>49% similarity)]. Given that one of the most striking differences between chimpanzees and humans is the increase in brain size, it is tempting to hypothesize that these mutations in ASB11 during human evolution enabled the species to acquire its superior cerebral power. In apparent agreement, functional studies have shown that ASB11 acts by enabling canonical Notch signaling (see Box 1 for a mechanistic explanation) 7, 8, whereas two recent articles published in Cell highlight the importance of canonical Notch signaling in explaining the evolution of the human brain 9, 10.