Oligodendrocytes are cells that myelinate axons, providing saltatory conduction of action potentials and proper function of the central nervous system. Myelination begins prenatally in the human, and the sequence of oligodendrocyte development and the onset of myelination are not thoroughly investigated. This knowledge is important to better understand human diseases, such as periventricular leukomalacia, one of the leading causes of motor defi cit in premature babies, and demyelinating disorders such as multiple sclerosis (MS). In this review we discuss the spatial and temporal progression of oligodendrocyte lineage characterized by the expression of specifi c markers and transcription factors in the human fetal brain from the early embryonic period (5 gestational weeks, gw) until midgestation (24 gw). Our in vitro evidence indicated that a subpopulation of human oligodendrocytes may have dorsal origin, from cortical radial glia cells, in addition to their ventral telencephalic origin. Furthermore, we demonstrated that the regulation of myelination in the human fetal brain includes positive and negative regulators. Chemokines, such as CXCL1, abundant in proliferative zones during brain development and in regions of remyelination in adult, are discussed in the view of their potential roles in stimulating oligodendrocyte development. Other signals are inhibitory and may include, but are not limited to, polysialic acid modifi cation of the neural cell adhesion molecule on axons. Overall, important differences in temporal and spatial distribution and regulatory signals for oligodendrocyte differentiation exist between human and rodent brains. Those differences may underlie the unique susceptibility of humans to demyelinating diseases, such as MS.

The cortical subventricular zone (SVZ), a proliferative compartment in the forebrain, has a uniquely important role during the second half of intrauterine development in human. This is best observed in numerous neonatal pathologies that result from prenatal SVZ damage. These conditions highlight a need to better understand the contribution of the SVZ to the development of the human cerebral cortex. With this goal in mind, we analyze histological organization, cell proliferation, and molecular diversity in the human fetal SVZ, from 7 to 27 gestational weeks (gw), using light and electron microscopy, immunohistochemistry, and in vitro methods. Complex histological organization distinguishes human cortical SVZ from that of other mammals. In vitro quantification showed that approximately 50% of cells in the VZ/SVZ region are neurons, 30% are astroglia, 15% are nestin + cells, with other cell types representing smaller fractions. Immunolabeling with BrdU, showed that a considerable number of cells (approximately 10%) are generated in the human cortical SVZ during midgestation (18-24gw), in in vitro conditions. Immunofluorescence with cell type specific markers and BrdU revealed that all major cell types, neural precursors (nestin + ), astroglia including radial glia (GFAP + , vimentin + ), and oligodendrocyte progenitors (PDGFR-α + ), were proliferating. An increase in the ratio of the size of the SVZ to VZ, protracted period of cell proliferation, as well as cellular and histological complexity of the human fetal SVZ, are directly related to the evolutionary expansion of the human cerebral cortex.

Understanding the molecular and physiological determinants of cortical neuronal progenitor cells is essential for understanding the development of the human brain in health and in disease. We used surface marker fucose N-acetyl lactosamine (LeX) (also known as CD15) to isolate progenitor cells from the cortical ventricular/subventricular zone of human fetal brain at the second trimester of gestation and to study their progeny in vitro.

Information about development of the human cerebral cortex (proliferation, migration, and differentiation of neurons) is largely based on postmortem histology. Physiological properties of developing human cortical neurons are difficult to access experimentally and therefore remain largely unexplored. Animal studies have shown that information about the arousal of electrical activity in individual cells within fundamental cortical zones (subventricular zone [SVZ], intermediate zone, subplate [SP], and cortical plate [CP]) is necessary for understanding normal brain development. Here we ask where, in what cortical zone, and when, in what gestational week (gw), human neurons acquire the ability to generate nerve impulses (action potentials [APs]). We performed electrical recordings from individual cells in acute brain slices harvested postmortem from the human fetal cerebral cortex (16-22 gw). Tetrodotoxin-sensitive Na(+) current occurs more frequently among CP cells and with significantly greater peak amplitudes than in SVZ. As early as 16 gw, a relatively small population of CP neurons (27%) was able to generate sodium APs upon direct current injection. Neurons located in the SP exhibited the highest level of cellular differentiation, as judged by their ability to fire repetitive APs. At 19 gw, a fraction of human CP and SP neurons possess beta IV spectrin-positive axon initial segments populated with voltage-gated sodium channels (PanNav). These results yield the first physiological characterization of developing human fetal cortical neurons with preserved morphologies in intact surrounding brain tissue.