Molecular Diversity of Midbrain Development in Mouse Human and Stem Cells

摘要

class="head no_bottom_margin" id="sec1title">IntroductionMuch of our current knowledge about brain development is based on the rodent brain. In the embryonic mouse ventricular zone (VZ), neuroepithelial stem cells differentiate into radial glia that will generate neurons, astrocytes, oligodendrocytes, and ependymal cells in successive waves of differentiation (). Analysis of mutant mice has revealed that morphogens such as WNT/β-catenin, SHH, and FGF8 induce regional-specific transcription factors at the midbrain-hindbrain boundary that provide nascent neuroblasts with defined dorso-ventral, antero-posterior, and mediolateral identities (). As a result, these neuroblasts mature into spatially defined mature populations, including dopaminergic neurons, oculomotor and trochlear neurons, and red nucleus neurons. The adult midbrain contains two main anatomically defined populations of dopaminergic neurons, located in the ventral tegmental area (VTA) and in the substantia nigra pars compacta (SNc) (). Notably, SNc neurons degenerate in Parkinson’s disease while the VTA suffers only a 40% reduction (, ).The development of the human ventral midbrain is currently thought to follow a similar sequence of events and principles as in rodent. However, the cell type composition and developmental programs that control the human ventral midbrain are largely unknown. It is also unclear what is the degree of conservation between mouse and human midbrain development and whether all cell types in human even have unambiguous counterparts in the mouse. In addition, several fundamental questions remain to be elucidated. First, it is unclear whether a single cell type (radial glia; ) can give rise to all the diverse progeny found in the ventral midbrain. Second, although five molecularly distinct dopaminergic neuron types have been recently described in the adult mouse (), it is unclear if these are specified in the embryo (e.g., using patterning morphogens) or if they emerge only postnatally (e.g., as a result of local environmental cues or feedback from innervation targets).Single-cell RNA-sequencing (RNA-seq) has been previously used for de novo cell type discovery in multiple tissues (, , , , ). Here, we use single-cell RNA-seq to examine ventral midbrain development in both mouse and human. Our results provide an unbiased classification of cell types and their gene expression patterns during human and mouse ventral midbrain development.