Sex-dependent interactions between prodromal intestinal inflammation and LRRK2 G2019S in mice promote endophenotypes of Parkinson's disease.

Gastrointestinal (GI) disruptions and inflammatory bowel disease (IBD) are commonly associated with Parkinson's disease (PD), but how they may impact risk for PD remains poorly understood. Herein, we provide evidence that prodromal intestinal inflammation expedites and exacerbates PD endophenotypes in rodent carriers of the human PD risk allele LRRK2 G2019S in a sex-dependent manner. Chronic intestinal damage in genetically predisposed male mice promotes α-synuclein aggregation in the substantia nigra, loss of dopaminergic neurons and motor impairment. This male bias is preserved in gonadectomized males, and similarly conferred by sex chromosomal complement in gonadal females expressing human LRRK2 G2019S. The early onset and heightened severity of neuropathological and behavioral outcomes in male LRRK2 G2019S mice is preceded by increases in α-synuclein in the colon, α-synuclein-positive macrophages in the colonic lamina propria, and loads of phosphorylated α-synuclein within microglia in the substantia nigra. Taken together, these data reveal that prodromal intestinal inflammation promotes the pathogenesis of PD endophenotypes in male carriers of LRRK2 G2019S, through mechanisms that depend on genotypic sex and involve early accumulation of α-synuclein in myeloid cells within the gut.

The Gut Microbiome as a Regulator of the Neuroimmune Landscape.

The gut microbiome influences many host physiologies, spanning gastrointestinal function, metabolism, immune homeostasis, neuroactivity, and behavior. Many microbial effects on the host are orchestrated by bidirectional interactions between the microbiome and immune system. Imbalances in this dialogue can lead to immune dysfunction and immune-mediated conditions in distal organs including the brain. Dysbiosis of the gut microbiome and dysregulated neuroimmune responses are common comorbidities of neurodevelopmental, neuropsychiatric, and neurological disorders, highlighting the importance of the gut microbiome-neuroimmune axis as a regulator of central nervous system homeostasis. In this review, we discuss recent evidence supporting a role for the gut microbiome in regulating the neuroimmune landscape in health and disease.

Signaling inflammation across the gut-brain axis.

The brain and gastrointestinal tract are critical sensory organs responsible for detecting, relaying, integrating, and responding to signals derived from the internal and external environment. At the interface of this sensory function, immune cells in the intestines and brain consistently survey environmental factors, eliciting responses that inform on the physiological state of the body. Recent research reveals that cross-talk along the gut-brain axis regulates inflammatory nociception, inflammatory responses, and immune homeostasis. Here, we discuss molecular and cellular mechanisms involved in the signaling of inflammation across the gut-brain axis. We further highlight interactions between the gut and the brain in inflammation-associated diseases.

Correction: Human bone marrow harbors cells with neural crest-associated characteristics like human adipose and dermis tissues.

[This corrects the article DOI: 10.1371/journal.pone.0177962.].

SnapShot: The microbiota-gut-brain axis.

Animals have co-evolved with a vast diversity of microorganisms, collectively named the microbiome, which are important modulators of host gastrointestinal, immune, metabolic, and behavioral functions. In this SnapShot, we provide an overview of the neurodevelopmental and functional influence of host-microbial interactions in the "microbiota-gut-brain axis," which refers to the bidirectional communication between the central nervous system and the gastrointestinal microbiome. To view this SnapShot, open or download the PDF.

A cell fitness selection model for neuronal survival during development.

Developmental cell death plays an important role in the construction of functional neural circuits. In vertebrates, the canonical view proposes a selection of the surviving neurons through stochastic competition for target-derived neurotrophic signals, implying an equal potential for neurons to compete. Here we show an alternative cell fitness selection of neurons that is defined by a specific neuronal heterogeneity code. Proprioceptive sensory neurons that will undergo cell death and those that will survive exhibit different molecular signatures that are regulated by retinoic acid and transcription factors, and are independent of the target and neurotrophins. These molecular features are genetically encoded, representing two distinct subgroups of neurons with contrasted functional maturation states and survival outcome. Thus, in this model, a heterogeneous code of intrinsic cell fitness in neighboring neurons provides differential competitive advantage resulting in the selection of cells with higher capacity to survive and functionally integrate into neural networks.

Principles of progenitor temporal patterning in the developing invertebrate and vertebrate nervous system.

During the development of the central nervous system, progenitors successively generate distinct types of neurons which assemble into the circuits that underlie our ability to interact with the environment. Spatial and temporal patterning mechanisms are partially evolutionarily conserved processes that allow generation of neuronal diversity from a limited set of progenitors. Here, we review examples of temporal patterning in neuronal progenitors in the Drosophila ventral nerve cord and in the mammalian cerebral cortex. We discuss cell-autonomous mechanisms and environmental influences on the temporal transitions of neuronal progenitors. Identifying the principles controlling the temporal specification of progenitors across species, as highlighted here, may help understand the evolutionary constraints over brain circuit design and function.

Cell-Intrinsic Control of Interneuron Migration Drives Cortical Morphogenesis.

Interneurons navigate along multiple tangential paths to settle into appropriate cortical layers. They undergo a saltatory migration paced by intermittent nuclear jumps whose regulation relies on interplay between extracellular cues and genetic-encoded information. It remains unclear how cycles of pause and movement are coordinated at the molecular level. Post-translational modification of proteins contributes to cell migration regulation. The present study uncovers that carboxypeptidase 1, which promotes post-translational protein deglutamylation, controls the pausing of migrating cortical interneurons. Moreover, we demonstrate that pausing during migration attenuates movement simultaneity at the population level, thereby controlling the flow of interneurons invading the cortex. Interfering with the regulation of pausing not only affects the size of the cortical interneuron cohort but also impairs the generation of age-matched projection neurons of the upper layers.

Cerebral cortex development: an outside-in perspective.

The cerebral cortex is a complex structure that contains different classes of neurons distributed within six layers and regionally organized into highly specialized areas. Cortical layering arises during embryonic development in an inside-out manner as forebrain progenitors proliferate and generate distinct waves of interneurons and projection neurons. Radial glial cells (RGCs) derive from neuroepithelial cells and are the founding cortical progenitors. At the onset of corticogenesis, RGCs expand their pool by proliferative divisions. As corticogenesis proceeds, they gradually undergo differentiative divisions to either generate neurons directly (direct neurogenesis) or indirectly via production of intermediate progenitors that further divide to generate pairs of neurons (indirect neurogenesis). The fate of RGCs is finely regulated during all the corticogenesis process and depends on time-scaled perception of external signals and expression of intrinsic factors. The present Review focuses on the role of physiological extracellular cues arising from the vicinity of neural progenitors on the regulation of dorsal neurogenesis and cerebral cortex patterning. It further discusses how pathogenic viral factors influence RGC behaviour and disrupt cerebral cortex development.

Human bone marrow harbors cells with neural crest-associated characteristics like human adipose and dermis tissues.

Adult neural crest stem-derived cells (NCSC) are of extraordinary high plasticity and promising candidates for use in regenerative medicine. Several locations such as skin, adipose tissue, dental pulp or bone marrow have been described in rodent, as sources of NCSC. However, very little information is available concerning their correspondence in human tissues, and more precisely for human bone marrow. The main objective of this study was therefore to characterize NCSC from adult human bone marrow. In this purpose, we compared human bone marrow stromal cells to human adipose tissue and dermis, already described for containing NCSC. We performed comparative analyses in terms of gene and protein expression as well as functional characterizations. It appeared that human bone marrow, similarly to adipose tissue and dermis, contains NESTIN+ / SOX9+ / TWIST+ / SLUG+ / P75NTR+ / BRN3A+/ MSI1+/ SNAIL1+ cells and were able to differentiate into melanocytes, Schwann cells and neurons. Moreover, when injected into chicken embryos, all those cells were able to migrate and follow endogenous neural crest migration pathways. Altogether, the phenotypic characterization and migration abilities strongly suggest the presence of neural crest-derived cells in human adult bone marrow.

Adult bone marrow mesenchymal and neural crest stem cells are chemoattractive and accelerate motor recovery in a mouse model of spinal cord injury.

INTRODUCTION: Stem cells from adult tissues were considered for a long time as promising tools for regenerative therapy of neurological diseases, including spinal cord injuries (SCI). Indeed, mesenchymal (MSCs) and neural crest stem cells (NCSCs) together constitute the bone marrow stromal stem cells (BMSCs) that were used as therapeutic options in various models of experimental SCI. However, as clinical approaches remained disappointing, we thought that reducing BMSC heterogeneity should be a potential way to improve treatment efficiency and reproducibility. METHODS: We investigated the impact of pure populations of MSCs and NCSCs isolated from adult bone marrow in a mouse model of spinal cord injury. We then analyzed the secretome of both MSCs and NCSCs, and its effect on macrophage migration in vitro. RESULTS: We first observed that both cell types induced motor recovery in mice, and modified the inflammatory reaction in the lesion site. We also demonstrated that NCSCs but especially MSCs were able to secrete chemokines and attract macrophages in vitro. Finally, it appears that MSC injection in the spinal cord enhance early inflammatory events in the blood and spinal cord of SCI mice. CONCLUSIONS: Altogether, our results suggest that both cell types have beneficial effects in experimental SCI, and that further investigation should be dedicated to the regulation of the inflammatory reaction following SCI, in the context of stem cell-based therapy but also in the early-phase clinical management of SCI patients.