Deciphering the core instructions of neuronal differentiation

Abstract

The amazing field of Developmental Neuroscience has provided fascinating insights into mechanisms regulating the generation of a huge array of different neuron populations. The discovery of a large set of growth factors influencing cellular differentiation choices and transcription factors regulating expression of genes specific to progenitor and neuron populations has been instrumental. The analysis has failed, however, to establish a clear idea on the acquisition of the common structural as well as information-propagating and -processing neuronal features during neurogenesis. Moreover, it is not resolved how this is coordinated with the diversification of the distinct neuron populations.Focusing attention on the early developmental expression of shared molecular players involved in formation of the neuronal cytoskeleton, generation of action potentials and regulation of neurotransmitter release has begun to change the field. Together with the recognition of several layers in the coordination of gene expression extending from (1) modification of nuclear and chromatin organization to (2) action of transcription regulator complexes at enhancer and promoter sequences to (3) posttranscriptional regulation by powerful non-coding RNA/protein networks, a comprehensive picture of the route from neural progenitor to neuron takes shape.Fueled by the observation that a limited set of regulators from each of these layers has the potential to drive neuronal differentiation in stem cells or even from unrelated cell types such as fibroblasts, the finding of developmental expression patterns of genes coding for neuronal cytoskeletal and synaptic proteins conserved across vertebrate neuron populations prompts the question for a shared generic differentiation program. Involvement of some of those regulators and expression of certain target genes in sensory receptor and endocrine cell differentiation may define a group of related signalcommunicating cells and further refine the core of a neuronal differentiation program. Comparison to invertebrate neural development demonstrating related functions of orthologous regulators will decipher the evolutionary core instructions on 'how to build a neuron'. The consequences of such a basic comprehension of generic neuronal differentiation for stem cell-derived tissue replacement approaches, as well as the neuro-pathological and neuro-oncological clinic, are of particular interest.The exciting search for the mechanisms governing neuronal development has received additional momentum by the goal to predictably tailor programming and reprogramming routines for cell and tissue replacement techniques. Both basic and applied approaches have uncovered or employed, respectively, regulatory schemes related to the diversification of the enormous variety of neuron classes. In order to generate a specific type of neuron in vitro this procedure has already proven successful. Yet Ninkovic and Götz (2014, this issue) discuss the question whether application of a common principle of neuronal differentia...

The development of early pioneer neurons in the annelid Malacoceros fuliginosus

“…The basic scheme of early neurogenesis, that is, the early steps in the development of individual neurons, depends in eumetazoans on a fairly conserved set of transcription factors, many of them belonging to the Sox and proneural bHLH gene families [ 1 , 2 ]. Though regulation and interdependency display variability between groups, these genes were in many organisms found to play important roles in neurogenesis: from providing neurogenic potential in the ectoderm of early embryos and controlling the step-wise transition of self-renewing multi-potential neuronal progenitors to more committed precursors which later differentiate into specific neurons or glia elements [ 3 – 6 ]. Where, when, and which neuronal types are formed depends on patterning processes, which are intimately linked to the above-described steps of neurogenesis and the subsequent process of differentiation, like broad anterior-posterior and dorso-ventral patterning of the ectoderm and more local patterning processes during subdomain development [ 7 – 11 ].…”

The development of early pioneer neurons in the annelid Malacoceros fuliginosus

“…The basic scheme of early neurogenesis, that is, the early steps in the development of individual neurons, depends in eumetazoans on a fairly conserved set of transcription factors, many of them belonging to the Sox and proneural bHLH gene families [1,2]. Though regulation and interdependency display variability between groups, these genes were in many organisms found to play important roles in neurogenesis: from providing neurogenic potential in the ectoderm of early embryos and controlling the step-wise transition of self-renewing multi-potential neuronal progenitors to more committed precursors which later differentiate into speci c neurons or glia elements [3][4][5][6]. Where, when, and which neuronal types are formed depends on patterning processes, which are intimately linked to the above-described steps of neurogenesis and the subsequent process of differentiation, like broad anterior-posterior and dorso-ventral patterning of the ectoderm and more local patterning processes during subdomain development [7][8][9][10][11]].…”

The neuron pioneering the ventral nerve cord does not follow the common pathway of neurogenesis in the polychaete Malacoceros fuliginosus

“…the early steps in the development of individual neurons, depends in eumetazoans on a fairly conserved set of transcription factors many of them belonging to the Sox and proneural bHLH gene families [1,2]. Though regulation and interdependency displays variability between groups, these genes were in many organisms found to play important roles in neurogenesis: from providing neurogenic potential in the ectoderm of early embryos and controlling the step-wise transition of self-renewing multi-potential neuronal progenitors to more committed precursors which later differentiate into specific neurons or glia elements [3][4][5][6]. Where, when and which neuronal types are formed depends on patterning processes, which are intimately linked to the above described steps of neurogenesis and the subsequent process of differentiation, like broad anterior-posterior and dorso-ventral patterning of the ectoderm and more local patterning processes during subdomain development [7][8][9][10][11]].…”