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What are the precise molecular and cellular mechanisms that the human brain exploits to encode consciousness, identity and thought? This undoubtedly remains one of the greatest scientific challenges facing mankind. Unravelling the structural and functional diversity of neurons, an estimated 1010 of which populate the cerebral cortex alone (Rakic, 2009), and explaining the molecular principles that integrate these cells into coherent and dynamic networks have been at the forefront of neuroscience research for the past century. Key inferences of our understanding include the following. Firstly, that each prospective neuron harbours the transcriptional code that defines its placement and basic structural and functional make-up (Fishell & Hanashima, 2008). Secondly, the computational power of the human brain is entrained by synapses, specialized junctions of communication. The placement of synapses is precisely defined during the growth of the axon (Song & Poo, 1999) that emerges from developing neurons to function as a conduit of electrical impulses representing packets of information. Thirdly, the continuous and ‘on-demand’ adaptation of synapses provides the substrate for learning and memory. Finally, excess pruning of synaptic contacts impairs the brain’s capacity to recruit an essential minimum of neurons into computational networks (Kantor & Kolodkin, 2003). This has the effect of preventing the execution of vital commands. The present Special Issue entitled ‘Molecular Mechanisms of Neuronal Specification’ encompasses 17 reviews and original research articles addressing these rules with eminent precision and attention to detail (Fig. 1). The emergence of primary ‘hot-spots’ derived from the converging interest of some of the leading neurodevelopmental research groups in this Special Issue is naturally exciting, and it is hoped that they will serve as guideposts for innovative studies for the years to come.

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Figure 1.  Successive stages of neuronal differentiation from early determination of neuronal subtypes to their wiring into neuronal networks. The articles in this Special Issue of the European Journal of Neuroscience were grouped thematically and are listed on the right. a.i.s., axon initial segment.

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This ensemble thematically opens by surveying the molecular regulation of the earliest events of nervous system development, when the neural and border domains of the embryonic ectoderm define the central and peripheral nervous systems respectively, and by outlining a novel model of how extracellular signals interact to coordinate the specification and regionalization of border cells (Patthey & Gunhaga, 2011).

Our attention then turns towards a series of original research and review articles providing a comprehensive account of the cell-autonomous and intercellular mechanisms to address how, where and when neuronal diversity is generated. Some of these studies focus on the formation of the cerebral cortex (Anastasiades & Butt, 2011; Antypa et al., 2011), whose uniquely ordered (laminated) cellular organization and functional precision to orchestrate specific behaviours relies on the timely migration and synaptic wiring of interneurons and pyramidal cells, and has fascinated many generations of neurobiologists. Molecular principles of GABAergic interneurons come to the fore as the unprecedented variety of these local-circuit components of cortical networks emphasizes that overarching cascades of instructive mechanisms must continuously operate to facilitate the attaining of neuronal identity (Anastasiades & Butt, 2011).

Three additional articles broaden the concept of the transcription factor requirements of neuronal differentiation into a general rule by showing central roles for Shox2 in the specification of discriminative touch-sensitive neurons in sensory dorsal root ganglia (Abdo et al., 2011), and transcriptional cascades converging on Lmx1b/Pet1 and giving rise to hindbrain serotonergic neurons (Kiyasova & Gaspar, 2011). A bone morphogenetic protein-induced network of transcription factors, with central roles for Ascl1 and Phox2b, with sequential expression is described as inducing autonomic neuron differentiation in sympathetic ganglia (Rohrer, 2011). A unifying theme of these articles is the fascinating concept that the expression of transcription factors, and their combinations, is fate instructive, required to prospectively determine the intrinsic molecular and electrical make-up of differentiated neurons, and their maintenance until adulthood is critical for the continued manifestation of neuronal subtype characteristics, as well as neuronal survival.

Intriguingly, Kiyasova & Gaspar (2011) put forward the hypothesis that neurons may rely on the very same transcription factors that instruct their identity (e.g. Pet1) to orchestrate axonal growth and guidance, and the formation of hierarchical synaptic connectivity maps. Nevertheless, unwavering efforts are directed to discover novel signalling networks that control neuronal migration (Antypa et al., 2011; Manent et al., 2011) and/or axonal growth and guidance (Chenaux & Henkemeyer, 2011; Oudin et al., 2011). The impact of furthering our understanding of molecular signalling events through the genetic dissection of bidirectional ligand–receptor interactions between the axon and its target is highlighted by Chenaux & Henkemeyer (2011), whose work closes in on the EphB–ephrin-B interaction during axonal pathfinding of retinal ganglion cells.

It is one thing to understand how a single axon navigates towards its target, but understanding the ordered growth of many axons to establish large-scale topologically precise sensory maps is entirely another. Here, Wu et al. (2011) discuss the myriad of diffusible axon guidance cues that orchestrate the precisely timed and topographically correct innervation of target cells during the formation of the whisker-to-barrel (somatosensory) cortex circuitry. In turn, Imai & Sakano (2011) propose the appealing model that the establishment of precise topographic maps in sensory systems is through the direct interplay and ‘self-organization’ of the growing afferent axons.

Is there a specific spatial resolution at which information must be gained to appreciate the range of signalling mechanisms in vivo? Antypa et al. (2011) have succeeded in exploiting the strength of high-throughput array technologies to elucidate the spatial constraints of instructive signals in relation to discrete subcontingents of developing neurons, and compared cell surface receptor expression and signalling pathways in spatially-segregated streams of tangentially migrating GABA interneurons in the neocortex.

This study, together with reviews by Oudin et al. (2011) and Morris et al. (2011), points to the endocannabinoid system, whose signalling competence is being appreciated as a novel force to reckon during neuronal migration, axonal growth and guidance, and synapse formation (Keimpema et al., 2011). The unexpected flavour of this story is that ectopic activation of cannabinoid receptors in the fetal brain by psychoactive components of marijuana during maternal abuse can impose life-long modifications on gene expression by introducing repressive epigenetic modifications (Morris et al., 2011).

This Special Issue also takes a closer look at rearrangements of the actin cytoskeleton (Manent et al., 2011; Menna et al., 2011) in relation to spatial navigation during cell migration (Manent et al., 2011), as well as the differentiation and stabilization of axons and dendrites during synapse formation (Menna et al., 2011). However, synaptic neurotransmission cannot progress without the developing neuron gaining the ability to generate action potentials and propagate these unidirectionally along its axon, a process strikingly reliant on the clustering of voltage-gated ion channels anchored by a specialized cytoskeletal scaffold in the axon initial segment just proximal to the soma (Buffington & Rasband, 2011). Synaptogenesis is followed by the onset of synaptic neurotransmission, with the formation of the first functional GABAergic synapses (Gozlan & Ben-Ari, 2003; Morozov et al., 2006) preceding the establishment of glutamatergic terminals (Tyzio et al., 1999). However, the maturation of neuronal networks continues for prolonged periods of postnatal development (measured in weeks in neonatal rodents). A series of contributions (Kilb et al., 2011; Sauer & Bartos, 2011; Watanabe & Kano, 2011) discusses here that the postnatal development of neurons is a delicate and dynamic process throughout the brain, and is associated with a dramatic reorganization of the neuronal cytoarchitecture, activity-dependent refinement of synaptic organization through the continued formation, translocation, selection and elimination of synapses, and switches in the modes of synaptic neurotransmission to optimize an individual neuron’s contribution to the neuronal network into which it is embedded. Kilb et al. (2011) highlight that the neocortical subplate, a transient structure, can amplify afferent sensory input to orchestrate patterned immature network activity. Thus, early neuronal activity will be efficacious in facilitating the continued recruitment of new neurons to emergent networks by regulating their migration and differentiation.

The significance of any developmental mechanism is best appreciated if negating its action manifests in irreparable developmental abnormalities (e.g. decreased neurogenesis, neuronal death, defunct neuronal migration, erroneous target innervation). This is a recurrent theme in this Special Issue since loss-of-function analysis is perceived by many investigators as the gold standard. Moreover, the detrimental effects of antiepileptic drugs, alcohol, cocaine (Manent et al., 2011), tobacco or cannabis (Morris et al., 2011; Oudin et al., 2011) are revealed and suggest life-long impairments to cognition (Buffington & Rasband, 2011), emotional control (Kiyasova & Gaspar, 2011) or sensory information processing (Abdo et al., 2011; Wu et al., 2011).

I hope this Special Issue appropriately reflects recent advances in developmental neurobiology, from the significant expansion of the genetic toolbox available to researchers to major concepts spurring broad interest due to their clinical relevance. Santiago Ramon y Cajal is quoted as saying, ‘The brain is a world consisting of a number of unexplored continents and great stretches of unknown territory’. I am confident that each contribution in this Special Issue represents an outstanding reference in its own right and will help to attract new generations of neurobiologists to explore, challenge and most notably reduce the extent of unknown territories in the developing nervous system.

Acknowledgements

  1. Top of page
  2. Acknowledgements
  3. References

I wish to thank the contributors who have submitted their work to this Special Issue of the European Journal of Neuroscience, allowing me to present a uniquely broad cross-section of developmental neurobiology. I also acknowledge the support of Jean-Marc Fritschy and Martin Sarter, editors-in-chief, as well as Sue Fromant and Sophie Gavarini, editorial managers, in successfully compiling this Special Issue.

References

  1. Top of page
  2. Acknowledgements
  3. References