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The study of cerebellar development has been at the forefront of neuroscience since the pioneering work of Wilhelm His Sr., Santiago Ramón y Cajal and many others since the 19th century. They laid the foundation to identify the circuitry of the cerebellum, already revealing its stereotypic three‐layered cortex and discerning several of its neuronal components. Their work was fundamental in the acceptance of the neuron doctrine, which acknowledges the key role of individual neurons in forming the basic units of the nervous system. Increasing evidence shows that the cerebellum performs a variety of homeostatic and higher order neuronal functions beyond the mere control of motor behaviour. Over the last three decades, many studies have revealed the molecular machinery that regulates distinct aspects of cerebellar development, from the establishment of a cerebellar anlage in the posterior brain to the identification of cerebellar neuron diversity at the single cell level. In this review, we focus on summarizing our current knowledge on early cerebellar development with a particular emphasis on the molecular determinants that secure neuron specification and contribute to the diversity of cerebellar neurons. [ABSTRACT FROM AUTHOR]

Endocytosis is an essential cellular process required for multiple physiological functions, including communication with the extracellular environment, nutrient uptake, and signaling by the cell surface receptors. In a broad sense, endocytosis is accomplished through either constitutive or ligand‐induced invagination of the plasma membrane, which results in the formation of the plasma membrane‐retrieved endocytic vesicles, which can either be sent for degradation to the lysosomes or recycled back to the PM. This additional function of endocytosis in membrane retrieval has been adopted by excitable cells, such as neurons, for membrane equilibrium maintenance at synapses. The last two decades were especially productive with respect to the identification of brain‐specific functions of the endocytic machinery, which additionally include but not limited to regulation of neuronal differentiation and migration, maintenance of neuron morphology and synaptic plasticity, and prevention of neurotoxic aggregates spreading. In this review, we highlight the current knowledge of brain‐specific functions of endocytic machinery with a specific focus on three brain cell types, neuronal progenitor cells, neurons, and glial cells. [ABSTRACT FROM AUTHOR]

The class II Rab11 family‐interacting proteins, FIP3 and FIP4, also termed Arfophilin‐1 and Arfophilin‐2, respectively, are endosomal proteins that function as dual effector proteins for Rab11 and ADP ribosylation factor (Arf) small GTPases. In the present study, we examined the expression and role of FIP4 in neuronal migration during cerebral layer formation. FIP4mRNA was first weakly detected in post‐mitotic migrating neurons in the upper intermediate zone, and expression was markedly increased in the cortical layer. Exogenously expressed FIP4 protein was localized to subpopulations of EEA1‐ and syntaxin 12‐positive endosomes in migrating neurons, and was partially colocalized with FIP3. Knockdown of FIP4 by in utero electroporation significantly stalled transfected neurons in the lower cortical layer and decreased the speed of neuronal migration in the upper intermediate zone and in the cortical plate compared with control small hairpin RNA (shRNA)‐transfected neurons. Furthermore, co‐transfection of shRNA‐resistant wild‐type FIP4, but not wild type FIP3 or FIP4 mutants lacking the binding region for Rab11 or Arf, significantly improved the disturbed cortical layer formation caused by FIP4 knockdown. Collectively, our findings suggest that FIP4 and FIP3 play overlapping but distinct roles in neuronal migration downstream of Arf and Rab11 during cortical layer formation. Family of Rab11‐interacting protein 4 (FIP4)/Arfophilin‐2 regulates neuronal migration in the upper intermediate zone and cortical plate through Arf‐ and Rab11‐dependent endosomal trafficking during cortical layer formation. [ABSTRACT FROM AUTHOR]

The midbrain GABAergic neurones control several aspects of behaviour, play important roles in psychiatric disease and are targets of medical treatments as well as drugs of abuse. However, their molecular diversity and regulation of development are only beginning to be understood. In this review, we briefly introduce distinct subpopulations of the midbrain GABAergic neurones and discuss knowledge on their development, including the developmental origins of midbrain GABAergic neurones as well as transcriptional regulatory mechanisms guiding their differentiation and identity. Important GABAergic neuron subpopulations are found within the dopaminergic (DA) nuclei in the ventral midbrain. GABAergic substantia nigra pars reticulata is the main output pathway of the basal ganglia system regulating voluntary movements. Recent studies have also highlighted importance of the GABAergic neurones associated with the ventral tegmental area for the control of DA neuron activity and motivated behaviours. Interestingly, the development of the GABAergic neurones associated with the DA nuclei is very different from the rest of the midbrain. Knowledge on developmental regulation can lead to insights into the molecular, structural and functional diversity of the midbrain GABAergic neurones and their subpopulations, cell groups of great physiological and medical interest. [ABSTRACT FROM AUTHOR]

The Pax6 transcription factor is expressed in cerebellar granule cells and when mutated, as in the Sey/Sey mouse, produces granule cells with disturbed survival and migration and with defects in neurite extension. The impact of Pax6 on other genes in the context of cerebellar development has not been identified. In this study, we performed transcriptome comparisons between wildtype and Pax6-null whole cerebellar tissue at embryonic day (E) 13.5, 15.5 and 18.5 using Affymetrix arrays (U74Av2). Statistical analyses identified 136 differentially regulated transcripts (FDR 0.05, 1.2-fold change cutoff) over time in Pax6-null cerebellar tissue. In parallel we examined the Math1-null granuloprival cerebellum and identified 228 down-regulated transcripts (FDR 0.05, 1.2-fold change cutoff). The intersection of these two microarray datasets produced a total of 21 differentially regulated transcripts. For a subset of the identified transcripts, we used qRT-PCR to validate the microarray data and demonstrated the expression in the rhombic lip lineage and differential expression in Pax6-null cerebellum with in situ hybridisation analysis. The candidate genes identified in this way represent direct or indirect Pax6-downstream genes involved in cerebellar development. [ABSTRACT FROM AUTHOR]

Abstract: Wilhelm His identified the rhombic lip in human embryos a century ago and thought that all mossy and climbing fiber neurons are derived from it. This has been accepted for more than one hundred years. However, recent genetic fate mapping studies have demonstrated that mossy fiber and climbing fiber neurons have distinct progenitor pools and originate from different subdomains in the ventricular zone of the caudal hindbrain. The majority of climbing fiber neurons has been found to derive from more medial parts of the caudal hindbrain although its dorsal boundary is unclear currently. Subsequently, several new definitions for the rhombic lip have been made according to the expression domain of different transcription factors, such as Math1, Wnt1 and Olig3, which have different ventral boundaries and make the area of rhombic lip confused. Therefore, a precise definition for rhombic lip is still lacking for the main reason that the origin of the entire inferior olivary nuclei is still unclear. Further genetic fate mapping is needed to determine the origin of all climbing fiber neurons which will help to give the rhombic lip an unambiguous definition. [Copyright &y& Elsevier]

Transcription factors (TFs) play pivotal roles in directing the formation of neurons and glia. Here I will review the recent genome-scale analysis of the expression of TFs in the developing mouse nervous system and discuss the logic by which TFs control the establishment of neuronal phenotype. Accumulating evidence suggests that while combinatorial action of TFs is able to define the basic framework of the nervous system, other control mechanisms, such as stochastic and epigenetic regulation of gene expression, also contribute to the generation of nerve cell diversity. [ABSTRACT FROM AUTHOR]