Lateral Motor Column specific expression of Sonic Hedgehog contributes to maintenance and scaling of pMN progenitor cell populations during oligodendrogenesis.

Motor neurons (MNs) and oligodendrocyte precursor cells (OPCs) emerge sequentially from the pMN precursor domain during spinal cord development. MNs diversify into muscle specific subtypes and settle in stereotypic locations in the ventral horns. In contrast, OPCs are mobile and appear to evenly populate the parenchyma. Whether earlier born MNs influence OPC production is controversial. We found that Sonic Hedgehog signaling emanating from nascent MNs of the lateral motor column is critical for maintaining a larger and more yielding pMN domain at limb levels compared to trunk levels during OPC production. Reduced Shh signaling resulted in unrecoverable diminishment of pMN domain based OPC production leaving the spinal cord impoverished of OPC. Our results suggest that production of OPC at limb levels is contingent on completion of MN production.

Quantitative Prediction of the Location of Carotid Bifurcation and Neurovascular Structures in the Carotid Region: A Cross-Sectional Cadaveric Study.

INTRODUCTION: The carotid region is encountered in vascular and neurological surgery and carries a potential for vascular and cranial nerve trauma. The carotid bifurcation is an especially important landmark and difficult to predict based on currently established landmarks. This study is a detailed analysis of the carotid region and proposes a novel methodology to predict the height of the bifurcation. MATERIALS AND METHODS: Superficial and deep dissections were performed on the anterior triangle of the neck to expose the carotid region in twenty-one formalin-fixed donor cadavers. Musculoskeletal and neurovascular structures were assessed in relation to the carotid bifurcation and the medial border of the clavicle (MBC). RESULTS: The carotid bifurcation occurred, on average, 11.4 mm higher on the left (p < 0.001; 95% CI: 9.28, 13.54). The superior thyroid artery (p < 0.001), facial vein (p < 0.001), and cranial nerve XII (p < 0.001) were all more distal on the left side when measured from the MBC while the angle of the mandible and stylohyoid muscle remained symmetric. Left- and right-sided vascular structures were symmetric when measured from the carotid bifurcation. CONCLUSIONS: Neurovascular structures within the carotid region are likely to be anatomically superior on the left side while vessels are likely to remain symmetric in relation to the carotid bifurcation. When measured from the MBC, the bifurcation height can be predicted by multiplying the distance between the MBC and mastoid process by 0.65 (right side) or 0.74 (left side). This novel methodological estimation may be easily learned and directly implemented in clinical practice.

Dopaminergic co-transmission with sonic hedgehog inhibits abnormal involuntary movements in models of Parkinson's disease and L-Dopa induced dyskinesia.

L-Dopa induced dyskinesia (LID) is a debilitating side effect of dopamine replacement therapy for Parkinson's Disease. The mechanistic underpinnings of LID remain obscure. Here we report that diminished sonic hedgehog (Shh) signaling in the basal ganglia caused by the degeneration of midbrain dopamine neurons facilitates the formation and expression of LID. We find that the pharmacological activation of Smoothened, a downstream effector of Shh, attenuates LID in the neurotoxic 6-OHDA- and genetic aphakia mouse models of Parkinson's Disease. Employing conditional genetic loss-of-function approaches, we show that reducing Shh secretion from dopamine neurons or Smoothened activity in cholinergic interneurons promotes LID. Conversely, the selective expression of constitutively active Smoothened in cholinergic interneurons is sufficient to render the sensitized aphakia model of Parkinson's Disease resistant to LID. Furthermore, acute depletion of Shh from dopamine neurons through prolonged optogenetic stimulation in otherwise intact mice and in the absence of L-Dopa produces LID-like involuntary movements. These findings indicate that augmenting Shh signaling in the L-Dopa treated brain may be a promising therapeutic approach for mitigating the dyskinetic side effects of long-term treatment with L-Dopa.

Diminished Ventral Oligodendrocyte Precursor Generation Results in the Subsequent Over-production of Dorsal Oligodendrocyte Precursors of Aberrant Morphology and Function.

Oligodendrocyte precursor cells (OPCs) arise sequentially first from a ventral and then from a dorsal precursor domain at the end of neurogenesis during spinal cord development. Whether the sequential production of OPCs is of physiological significance has not been examined. Here we show that ablating Shh signaling from nascent ventricular zone derivatives and partially from the floor plate results in a severe diminishment of ventral derived OPCs but normal numbers of motor neurons in the postnatal spinal cord. In the absence of ventral vOPCs, dorsal dOPCs populate the entire spinal cord resulting in an increased OPC density in the ventral horns. These OPCs take on an altered morphology, do not participate in the removal of excitatory vGlut1 synapses from injured motor neurons, and exhibit morphological features similar to those found in the vicinity of motor neurons in the SOD1 mouse model of Amyotrophic Lateral Sclerosis (ALS). Our data indicate that vOPCs prevent dOPCs from invading ventral spinal cord laminae and suggest that vOPCs have a unique ability to communicate with injured motor neurons.

Sonic Hedgehog is expressed by hilar mossy cells and regulates cellular survival and neurogenesis in the adult hippocampus.

Sonic hedgehog (Shh) is a multifunctional signaling protein governing pattern formation, proliferation and cell survival during embryogenesis. In the adult brain, Shh has neurotrophic function and is implicated in hippocampal neurogenesis but the cellular source of Shh in the hippocampus remains ill defined. Here, we utilize a gene expression tracer allele of Shh (Shh-nlacZ) which allowed the identification of a subpopulation of hilar neurons known as mossy cells (MCs) as a prominent and dynamic source of Shh within the dentate gyrus. AAV-Cre mediated ablation of Shh in the adult dentate gyrus led to a marked degeneration of MCs. Conversely, chemical stimulation of hippocampal neurons using the epileptogenic agent kainic acid (KA) increased the number of Shh+ MCs indicating that the expression of Shh by MCs confers a survival advantage during the response to excitotoxic insults. In addition, ablation of Shh in the adult dentate gyrus led to increased neural precursor cell proliferation and their migration into the subgranular cell layer demonstrating that MCs-generated Shh is a key modulator of hippocampal neurogenesis.

A Non-Cell-Autonomous Role of BEC-1/BECN1/Beclin1 in Coordinating Cell-Cycle Progression and Stem Cell Proliferation during Germline Development.

The decision of stem cells to proliferate and differentiate is finely controlled. The Caenorhabditis elegans germline provides a tractable system for studying the mechanisms that control stem cell proliferation and homeostasis [1-4]. Autophagy is a conserved cellular recycling process crucial for cellular homeostasis in many different contexts [5], but its function in germline stem cell proliferation remains poorly understood. Here, we describe a function for autophagy in germline stem cell proliferation. We found that autophagy genes such as bec-1/BECN1/Beclin1, atg-16.2/ATG16L, atg-18/WIPI1/2, and atg-7/ATG7 are required for the late larval expansion of germline stem cell progenitors in the C. elegans gonad. We further show that BEC-1/BECN1/Beclin1 acts independently of the GLP-1/Notch or DAF-7/TGF-ß pathways but together with the DAF-2/insulin IGF-1 receptor (IIR) signaling pathway to promote germline stem cell proliferation. Similar to DAF-2/IIR, BEC-1/BECN1/Beclin1, ATG-18/WIPI1/2, and ATG-16.2/ATG16L all promote cell-cycle progression and are negatively regulated by the phosphatase and tensin homolog DAF-18/PTEN. However, whereas BEC-1/BECN1/Beclin1 acts through the transcriptional regulator SKN-1/Nrf1, ATG-18/WIPI1/2 and ATG-16.2/ATG16L exert their function through the DAF-16/FOXO transcription factor. In contrast, ATG-7 functions in concert with the DAF-7/TGF-ß pathway to promote germline proliferation and is not required for cell-cycle progression. Finally, we report that BEC-1/BECN1/Beclin1 functions non-cell-autonomously to facilitate cell-cycle progression and stem cell proliferation. Our findings demonstrate a novel non-autonomous role for BEC-1/BECN1/Beclin1 in the control of stem cell proliferation and cell-cycle progression, which may have implications for the understanding and development of therapies against malignant cell growth in the future.