Deterministic HOX patterning in human pluripotent stem cell-derived neuroectoderm.
Bottom Line: Despite the precision of HOX patterning in vivo, in vitro approaches for differentiating human pluripotent stem cells (hPSCs) to posterior neural fates coarsely pattern HOX expression thereby generating cultures broadly specified to hindbrain or spinal cord regions.Here, we demonstrate that successive activation of fibroblast growth factor, Wnt/β-catenin, and growth differentiation factor signaling during hPSC differentiation generates stable, homogenous SOX2(+)/Brachyury(+) neuromesoderm that exhibits progressive, full colinear HOX activation over 7 days.This fully defined approach significantly expands capabilities to derive regional neural phenotypes from diverse hindbrain and spinal cord domains.
Affiliation: Department of Biomedical Engineering, University of Wisconsin, Madison, WI 53706, USA; Wisconsin Institute for Discovery, University of Wisconsin, Madison, WI 53706, USA.Show MeSH
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Mentions: The human genome contains 39 HOX genes divided among four clusters and classified into 13 paralogous groups based on sequence homology (Figure 1A). During embryonic stages of body axis elongation, newly formed tissues express HOX genes in sequential, contiguous domains consistent with their order in each cluster, i.e., colinearly. This phenomenon is evolutionarily conserved in bilaterian species and spatially assigns body segment-specific differentiation trajectories to axial progenitors of all three germ layers (Lewis, 1978). During formation of the posterior CNS, progenitors proximal to the node progressively transition from a 3′ to 5′ HOX expression profile as the primitive streak regresses (Iimura and Pourquié, 2006). This process produces nested and overlapping axial domains of HOX expression within the neuroepithelium of hindbrain rhombomeric (HOX1-5) and spinal cord cervical (HOX5-9), thoracic (HOX9-10), and lumbosacral (HOX10-13) vertebral segments (Figure 1A) (Philippidou and Dasen, 2013). The spatial variation of HOX expression along the rostrocaudal (R/C) axis of the posterior CNS diversifies the fates of neuroepithelial progeny and precisely restricts the development of specific neural subtypes to discrete axial positions (Philippidou and Dasen, 2013).
Affiliation: Department of Biomedical Engineering, University of Wisconsin, Madison, WI 53706, USA; Wisconsin Institute for Discovery, University of Wisconsin, Madison, WI 53706, USA.