Here, the mossy fiber-to-granule cell pathway could favor combinatorial processing and pattern discrimination, as suggested by Albus 72, Ito 73, and Marr 74

Here, the mossy fiber-to-granule cell pathway could favor combinatorial processing and pattern discrimination, as suggested by Albus 72, Ito 73, and Marr 74. these normal and abnormal processes, and how might they accomplish these seemingly disparate functions? The tiny but numerous cerebellar granule cells may hold answers to these questions. Here, we discuss recent advances in understanding how the granule cell lineage arises in the embryo and how a stem cell niche that replenishes granule cells influences wiring when the postnatal cerebellum is usually injured. We discuss how precisely coordinated developmental programs, gene expression patterns, and epigenetic mechanisms determine the formation of synapses that integrate multi-modal inputs onto single granule cells. These data lead us to consider how granule cell synaptic heterogeneity promotes sensorimotor and non-sensorimotor signals in behaving animals. We discuss evidence that granule cells use ultrafast neurotransmission that can operate at kilohertz frequencies. Together, these data inspire OAC1 an emerging view for how granule cells contribute to the shaping of complex animal behaviors. ( is not the only gene whose expression is usually specific for the rhombic lip. Other genes such as compartmentalize the rhombic lip into distinct molecular domains 17C 20. The elegant use of quail-chick chimeras allowed a careful analysis of how granule cell precursors are produced and migrate away from the rhombic lip to populate the external granular layer ( Physique 3B) 21. The external granular layer is usually a secondary germinal zone that produces the millions of granule cell progenitors that will later differentiate and then migrate into the core of the cerebellum using Bergmann glia astrocytes as a guide 22. Sonic hedgehog (Shh) 23, through Gli2 signaling 24, is required for granule cell proliferation, and recent work shows that the transcription factor Meis1 controls granule cell precursor differentiation through a Pax6CBmp OAC1 pathway that functions to degrade Atoh1 25. One of the major breakthroughs in the field was the demonstration that this rhombic lip gives rise to more Fam162a than just the granule cells. A combination of knock-in and knock-out mice as well as genetic inducible lineage-tracing techniques was used to show that this rhombic lip also produces the projection neurons of the cerebellar nuclei and the unipolar brush cells 10C 12, 19. These data indicated that this rhombic lip produces all of the glutamatergic neuronal classes of the cerebelluma finding that was supported by showing that this ventricular zone produces all the GABAergic neurons of the cerebellum 26. The specification of neuronal fates and the identities of the inhibitory versus excitatory neuronal classes are maintained by function in the ventricular zone and in the rhombic lip 27. Indeed, genetic removal of is enough to transform ventricular zone progenitors into a granule cell-like phenotype 28. Taken together, OAC1 the genetic cascades that orchestrate the embryonic stages of granule cell development set in place a morphogenetic program that allows the cerebellum to grow in size, organize its circuitry, and attain its characteristic folded morphology ( Physique 3). Physique 3. Open in a separate window Development of the cerebellar cortical layers.( A) A schematic depicting the embryonic brain with the cerebellum highlighted in color. ( B) A sagittal section from an embryonic day 16 brain with the cell bodies of neurons labeled using a Nissl stain (violet). The densely labeled external granular layer (green arrowhead, egl) and rhombic lip (green arrowhead, rl) are visible. ( C) A schematic depicting the adult brain with the cerebellum highlighted in color. ( D) A sagittal section from an adult brain with the cell bodies of neurons labeled using a Nissl stain (violet) and Purkinje cells labeled using calbindin immunohistochemistry (brown). The densely labeled granule cells are visible in the innermost layer of the cerebellar cortex, and the Purkinje cell somas and dendrites are visible in the outer layers of the cerebellar cortex. Roman numerals identify the 10 lobules. ( E) A magnified view of ( D). Scale bars = ( B) 100 m, ( D) 500 m, and ( E) 50 m. BS, brainstem; Cb, cerebellum; cp, choroid plexus; Ctx, cerebral cortex; gl, granular layer; Mb, midbrain; ml, molecular layer; pcl, Purkinje cell layer; SC, spinal cord. Granule cells are critical for postnatal morphogenesis The folded external gross morphology of the cerebellar cortex into lobules is usually a conserved feature that makes this structure easily recognizable in warm-blooded vertebrates 29. There are 10 major.