Modeling Mammalian Commitment to the Neural Lineage Using Embryos and Embryonic Stem Cells

Abstract

Early mammalian embryogenesis relies on a large range of cellular and molecular mechanisms to guide cell fate. In this highly complex interacting system, molecular circuitry tightly controls emergent properties, including cell differentiation, proliferation, morphology, migration, and communication. These molecular circuits include those responsible for the control of gene and protein expression, as well as metabolism and epigenetics. Due to the complexity of this circuitry and the relative inaccessibility of the mammalian embryo in utero , mammalian neural commitment remains one of the most challenging and poorly understood areas of developmental biology. In order to generate the nervous system, the embryo first produces two pluripotent populations, the inner cell mass and then the primitive ectoderm. The latter is the cellular substrate for gastrulation from which the three multipotent germ layers form. The germ layer definitive ectoderm, in turn, is the substrate for multipotent neurectoderm (neural plate and neural tube) formation, representing the first morphological signs of nervous system development. Subsequent patterning of the neural tube is then responsible for the formation of most of the central and peripheral nervous systems. While a large number of studies have assessed how a competent neurectoderm produces mature neural cells, less is known about the molecular signatures of definitive ectoderm and neurectoderm and the key molecular mechanisms driving their formation. Using pluripotent stem cells as a model, we will discuss the current understanding of how the pluripotent inner cell mass transitions to pluripotent primitive ectoderm and sequentially to the multipotent definitive ectoderm and neurectoderm. We will focus on the integration of cell signaling, gene activation, and epigenetic control that govern these developmental steps, and provide insight into the novel growth factor-like role that specific amino acids, such as L-proline, play in this process.

Selected Amino Acids Promote Mouse Pre-implantation Embryo Development in a Growth Factor-Like Manner

“…Furthermore, given the competitive inhibition profile is different, the transporter involved appears to be different. This is not surprising given that embryos dynamically express a range of aminoacid transporters in the pre-implantation stages (Van Winkle, 2001) suggesting they temporally exploit the use of different amino acids to promote key events in normal development (Shparberg et al, 2019b).…”

The Dynamic Proteome of Oligodendrocyte Lineage Differentiation Features Planar Cell Polarity and Macroautophagy Pathways

“…Glu can be used in Gln synthesis by glutamine synthetase (GLUL), an enzyme that has been shown to be involved in cell proliferation, and demonstrated a considerable expression in all steps of OL lineage differentiation (data not shown) [ 92 ]. On the basis of previous studies, Gln and Asn act as principal survival and self-renewal factors in ESCs and cancer cells, respectively [ 91 , 93 , 94 ]. Ryu et al.…”

Single‐cell study of neural stem cells derived from human iPSCs reveals distinct progenitor populations with neurogenic and gliogenic potential

“…In this perspective, reference genes can be used to identify and classify cell types along the temporal and spatial axis of embryonic central nervous system (CNS) development. The CNS developmental process can be modeled and mimicked with embryonic stem (ES) cells and iPS cells when induced toward NSC lines with above‐mentioned protocols (for reviews see Mertens et al, ; Shparberg, Glover, & Morris, ). Emerging functional cell types in the CNS can be classified by gene expression, for example, for the neurogenic lineage: DCX for neuroblasts (Gleeson, Lin, Flanagan, & Walsh, ), GAD2 for inhibitory neurons (McBain & Fisahn, ; Taniguchi et al, ), NPTX2 for synaptic priming of excitatory neurons (Pelkey et al, ), SLC17A6 (vGLUT2) for excitatory neurons (Fremeau, Voglmaier, Seal, & Edwards, ), LMX1B for dopaminergic neurons (Nakatani, Kumai, Mizuhara, Minaki, & Ono, ) and for the gliogenic lineage, PTPRZ1 for radial glia (Pollen et al, ) and FABP7 for astroglia (Ebrahimi et al, ).…”