SCHIZOPHRENIA EVOM CODE

hPSCs were first specified to dorsal and ventral progenitors in the absence (for dorsal) or presence (for ventral) of sonic hedgehog (SHH) signaling. Regionally defined astrocytes were generated from hPSCs according to our previous established protocols ( Fig. 1A) ( Krencik et al., 2011 Krencik and Zhang, 2011). As the same regionally specified neural progenitors give rise to glial cells after neurogenesis ( Freeman, 2010 Molofsky and Deneen, 2015), we hypothesized that the regional identity of astrocytes is established during progenitor specification. Neurons exhibit molecular and functional traits that are specific to their CNS region. In addition, these studies do not allow for the determination of the impact of developmental specification on regional astrocyte heterogeneity. Studies of regional astrocytes using human samples have focused on marker gene expression and have lacked functional analysis ( Oberheim et al., 2012).

Transcriptomic analysis of fetal and adult human astrocytes has been instrumental for increasing our understanding of human astrocyte development but has necessarily lacked analysis of regional subtypes ( Zhang et al., 2016). These studies give a rationale for the investigation of human astrocyte subtypes and their role in the development and pathogenesis of the human brain. Chimerization of the mouse forebrain at postnatal day (P)0 with human astrocytes results in adult mice that have increased synaptic transmission in the hippocampus and are able to learn faster than their allografted littermates ( Han et al., 2013). In addition to their size, there are functional differences between mouse and human astrocytes. The ratio of astrocytes to neurons is also increased in humans to approximately 1.65 astrocytes for every neuron, making astrocytes the primary cell type of the human cortex ( Nedergaard et al., 2003). Human cortical astrocytes are nearly three times larger than their mouse counterparts and extend roughly ten times the number of processes ( Oberheim et al., 2009). Although these studies are important, comparisons of mouse and human astrocytes have found meaningful differences. Studies of astrocyte heterogeneity have been conducted using mice. The functional properties of the regional astrocytes, however, remain largely unknown. Thus, both developmental origins and interactions with neighboring cells contribute to the phenotypes of regional astrocytes. Recent studies suggest that neighboring cells, including neurons, may instruct astrocytes to adopt a particular phenotype ( Farmer et al., 2016).

SCHIZOPHRENIA EVOM CODE

These results suggest a role of transcriptional code for position-restricted astrocyte specification. In addition, knockout of NKX6-1 in glial fibrillary acidic protein (GFAP)-expressing cells during development results in a lower number of astrocytes only in the ventral regions of the spinal cord ( Zhao et al., 2014).

Similarly, mis-expression of neuronal transcription factors Pa圆, Olig2 and Nkx2-2 disrupts the localization (migration) of reelin-expressing (dorso-lateral) and Slit1-expressing (ventro-medial) astrocytes ( Hochstim et al., 2008). Knockout or forced expression of the basic helix-loop-helix (bHLH) transcription factor stem cell leukemia (SCL also known as Tal1) regulates the generation of the S100β+ cells in the embryonic spinal cord ( Muroyama et al., 2005). How these traits are acquired is not entirely clear. Astrocytes in different regions of the mouse central nervous system (CNS) exhibit distinct gene expression profiles and potentially also differential functions, including the expression of glutamate transporters, synaptic modulating genes and support of different neuronal subtypes ( Bachoo et al., 2004 Morel et al., 2017 Regan et al., 2007).

Schizophrenia evom