From Bipotent Neuromesodermal Progenitors to Neural-Mesodermal Interactions during Embryonic Development

To ensure the formation of a properly patterned embryo, multiple processes must operate harmoniously at sequential phases of development. This is implemented by mutual interactions between cells and tissues that together regulate the segregation and specification of cells, their growth and morphogenesis. The formation of the spinal cord and paraxial mesoderm derivatives exquisitely illustrate these processes. Following early gastrulation, while the vertebrate body elongates, a population of bipotent neuromesodermal progenitors resident in the posterior region of the embryo generate both neural and mesodermal lineages. At later stages, the somitic mesoderm regulates aspects of neural patterning and differentiation of both central and peripheral neural progenitors. Reciprocally, neural precursors influence the paraxial mesoderm to regulate somite-derived myogenesis and additional processes by distinct mechanisms. Central to this crosstalk is the activity of the axial notochord, which, via sonic hedgehog signaling, plays pivotal roles in neural, skeletal muscle and cartilage ontogeny. Here, we discuss the cellular and molecular basis underlying this complex developmental plan, with a focus on the logic of sonic hedgehog activities in the coordination of the neural-mesodermal axis.

The Role of Sonic Hedgehog Pathway in the Development of the Central Nervous System and Aging-Related Neurodegenerative Diseases

The Sonic hedgehog (SHH) pathway affects neurogenesis and neural patterning during the development of the central nervous system. Dysregulation of the SHH pathway in the brain contributes to aging-related neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. At present, the SHH signaling pathway can be divided into the canonical signaling pathway and non-canonical signaling pathway, which directly or indirectly mediates other related pathways involved in the development of neurodegenerative diseases. Hence, an in-depth knowledge of the SHH signaling pathway may open an avenue of possibilities for the treatment of neurodegenerative diseases. Here, we summarize the role and mechanism of the SHH signaling pathway in the development of the central nervous system and aging-related neurodegenerative diseases. In this review, we will also highlight the potential of the SHH pathway as a therapeutic target for treating neurodegenerative diseases.

The CATP-8/P5A-type ATPase functions in multiple pathways during neuronal patterning

The assembly of neuronal circuits involves the migrations of neurons from their place of birth to their final location in the nervous system, as well as the coordinated growth and patterning of axons and dendrites. In screens for genes required for patterning of the nervous system, we identified the catp-8/P5A-ATPase as an important regulator of neural patterning. P5A-ATPases are part of the P-type ATPases, a family of proteins known to serve a conserved function as transporters of ions, lipids and polyamines in unicellular eukaryotes, plants, and humans. While the function of many P-type ATPases is relatively well understood, the function of P5A-ATPases in metazoans remained elusive. We show here, that the Caenorhabditis elegans ortholog catp-8/P5A-ATPase is required for defined aspects of nervous system development. Specifically, the catp-8/P5A-ATPase serves functions in shaping the elaborately sculpted dendritic trees of somatosensory PVD neurons. Moreover, catp-8/P5A-ATPase is required for axonal guidance and repulsion at the midline, as well as embryonic and postembryonic neuronal migrations. Interestingly, not all axons at the midline require catp-8/P5A-ATPase, although the axons run in the same fascicles and navigate the same space. Similarly, not all neuronal migrations require catp-8/P5A-ATPase. A CATP-8/P5A-ATPase reporter is localized to the ER in most, if not all, tissues and catp-8/P5A-ATPase can function both cell-autonomously and non-autonomously to regulate neuronal development. Genetic analyses establish that catp-8/P5A-ATPase can function in multiple pathways, including the Menorin pathway, previously shown to control dendritic patterning in PVD, and Wnt signaling, which functions to control neuronal migrations. Lastly, we show that catp-8/P5A-ATPase is required for localizing select transmembrane proteins necessary for dendrite morphogenesis. Collectively, our studies suggest that catp-8/P5A-ATPase serves diverse, yet specific, roles in different genetic pathways and may be involved in the regulation or localization of transmembrane and secreted proteins to specific subcellular compartments.

Hif1α is required for Wnt regulated gene expression during Xenopus tropicalis tail regeneration

Regeneration of complex tissues is initiated by an injury-induced stress response, eventually leading to activation of developmental signaling pathways, such as Wnt signaling. How early injury cues are interpreted and coupled to activation of these developmental signals and their targets is not well understood. Here, we show that Hif1α, a stress induced transcription factor, is required for tail regeneration in Xenopus tropicalis. We find that Hif1α is required for regeneration of differentiated axial tissues, including axons and muscle. Using RNA-sequencing, we find that Hif1α and Wnt converge on a broad set of genes required for posterior specification and differentiation, including the posterior hox genes. We further show that Hif1α is required for transcription via a Wnt-responsive element, a function that is conserved in both regeneration and early neural patterning. Our findings indicate a regulatory role for Hif1α in Wnt mediated gene expression across multiple tissue contexts.

Wnt3 distribution in the zebrafish brain is determined by expression, diffusion and multiple molecular interactions

Wnt3 proteins are lipidated and glycosylated signaling molecules that play an important role in zebrafish neural patterning and brain development. However, the transport mechanism of lipid-modified Wnts through the hydrophilic extracellular environment for long-range action remains unresolved. Here we determine how Wnt3 accomplishes long-range distribution in the zebrafish brain. First, we characterize the Wnt3-producing source and Wnt3-receiving target regions. Subsequently, we analyze Wnt3 mobility at different length scales by fluorescence correlation spectroscopy and fluorescence recovery after photobleaching. We demonstrate that Wnt3 spreads extracellularly and interacts with heparan sulfate proteoglycans (HSPG). We then determine the binding affinity of Wnt3 to its receptor, Frizzled1 (Fzd1), using fluorescence cross-correlation spectroscopy and show that the co-receptor, low-density lipoprotein receptor-related protein 5 (Lrp5), is required for Wnt3-Fzd1 interaction. Our results are consistent with the extracellular distribution of Wnt3 by a diffusive mechanism that is modified by tissue morphology, interactions with HSPG, and Lrp5-mediated receptor binding, to regulate zebrafish brain development.

The development of early pioneer neurons in the annelid Malacoceros fuliginosus

Background Nervous system development is an interplay of many processes: the formation of individual neurons, which depends on whole-body and local patterning processes, and the coordinated growth of neurites and synapse formation. While knowledge of neural patterning in several animal groups is increasing, data on pioneer neurons that create the early axonal scaffold are scarce. Here we studied the first steps of nervous system development in the annelid Malacoceros fuliginosus. Results We performed a dense expression profiling of a broad set of neural genes. We found that SoxB expression begins at 4 h postfertilization, and shortly later, the neuronal progenitors can be identified at the anterior and the posterior pole by the transient and dynamic expression of proneural genes. At 9 hpf, the first neuronal cells start differentiating, and we provide a detailed description of axonal outgrowth of the pioneer neurons that create the primary neuronal scaffold. Tracing back the clonal origin of the ventral nerve cord pioneer neuron revealed that it is a descendant of the blastomere 2d (2d221), which after 7 cleavages starts expressing Neurogenin, Acheate-Scute and NeuroD. Conclusions We propose that an anterior and posterior origin of the nervous system is ancestral in annelids. We suggest that closer examination of the first pioneer neurons will be valuable in better understanding of nervous system development in spirally cleaving animals, to determine the potential role of cell-intrinsic properties in neuronal specification and to resolve the evolution of nervous systems.

Neural and Hormonal Control of Sexual Behavior

Gonadal hormones contribute to the sexual differentiation of brain and behavior throughout the lifespan, from initial neural patterning to “activation” of adult circuits. Sexual behavior is an ideal system in which to investigate the mechanisms underlying hormonal activation of neural circuits. Sexual behavior is a hormonally regulated, innate social behavior found across species. Although both sexes seek out and engage in sexual behavior, the specific actions involved in mating are sexually dimorphic. Thus, the neural circuits mediating sexual motivation and behavior in males and females are overlapping yet distinct. Furthermore, sexual behavior is strongly dependent on circulating gonadal hormones in both sexes. There has been significant recent progress on elucidating how gonadal hormones modulate physiological properties within sexual behavior circuits with consequences for behavior. Therefore, in this mini-review we review the neural circuits of male and female sexual motivation and behavior, from initial sensory detection of pheromones to the extended amygdala and on to medial hypothalamic nuclei and reward systems. We also discuss how gonadal hormones impact the physiology and functioning of each node within these circuits. By better understanding the myriad of ways in which gonadal hormones impact sexual behavior circuits, we can gain a richer and more complete appreciation for the neural substrates of complex behavior.

The development of early pioneer neurons in the annelid Malacoceros fuliginosus

Background Nervous system development is an interplay of many processes: the formation of individual neurons, which depends on whole-body and local patterning processes, and the coordinated growth of neurites and synapse formation. While knowledge of neural patterning in several animal groups is increasing, data on pioneer neurons that create the early axonal scaffold are scarce. Here we studied the first steps of nervous system development in the annelid Malacoceros fuliginosus . Results Here, we performed a dense expression profiling of a broad set of neural genes. We found that SoxB expression begins at 4 hours postfertilization, and shortly later, the neuronal progenitors can be identified at the anterior and the posterior pole by the transient and dynamic expression of proneural genes. At 9 hpf, the first neuronal cells start differentiating, and we provide a detailed description of axonal outgrowth of the pioneer neurons that create the primary neuronal scaffold. Tracing back the clonal origin of the ventral nerve cord pioneer neuron revealed that it is a descendant of the blastomere 2d (2d 221 ), which after 7 cleavages starts expressing Neurogenin , Achaete-Scute and NeuroD . Conclusions We propose that an anterior and posterior origin of the nervous system is ancestral in annelids. The specification of the relevant neurons starts very early and we suggest that closer examination of the first pioneer neurons will be valuable in better understanding of nervous system development in spirally cleaving animals, to determine the potential role of cell-intrinsic properties in neuronal specification and to resolve the evolution of nervous systems.