Defining The Role Of The Reelin Signaling Pathway In Neurogenesis And Behavior A Zebrafish Model Of Autism Spectrum Disorders

Defining the Role of the Reelin Signaling Pathway in Neurogenesis and Behavior - a Zebrafish Model of Autism Spectrum Disorders

The Neurobiology of Schizophrenia

The Neurobiology of Schizophrenia begins with an overview of the various facets and levels of schizophrenia pathophysiology, ranging systematically from its genetic basis over changes in neurochemistry and electrophysiology to a systemic neural circuits level. When possible, the editors point out connections between the various systems. The editors also depict methods and research strategies used in the respective field. The individual backgrounds of the two editors promote a synthesis between basic neuroscience and clinical relevance. - Provides a comprehensive overview of neurobiological aspects of schizophrenia - Discusses schizophrenia at behavioral, cognitive, clinical, electrophysiological, molecular, and genetic levels - Edited by a translational researcher and a psychiatrist to promote synthesis between basic neuroscience and clinical relevance - Elucidates connections between the various systems depicted, when possible

MET Signaling is Required for Multiple Aspects of Zebrafish Hindbrain Morphogenesis

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that is being diagnosed at increasing rates among young children. ASD is thought to have a genetic basis that leads to the abnormal development of neural networks. The search for genes that increase susceptibility to ASD has yielded many candidate genes, including several components of the MET signaling pathway. One promising candidate gene is MET, a receptor tyrosine kinase, which is activated by the ligand hepatocyte growth factor (HGF). Met-deficient mouse and chick models display abnormal development of the brain. Campbell et al., (2006) showed that ASD patients from a multiplex family were more likely to have a C allele instead of a G allele at a SNP in the 5' promoter region of MET compared to ASD patients from a simplex family; furthermore, the C allele was found to confer half of the normal transcription activity in transcription assays. Based on these studies, we established a zebrafish model to study Met signaling in the zebrafish hindbrain in order to find novel mechanisms involving met signaling and neurogenesis. First, we found that met, hgf1, and hgf2 mRNA are expressed in the zebrafish hindbrain during early somitogenesis. More specifically, met is expressed in the cerebellar primordium, including a subset of ventricular zone (VZ) progenitors. Hgf1 and hgf2 are also expressed in endoderm tissues underlying the neural tube. When we knocked down Met signaling by injecting morpholinos targeting met, hgf1, or hgf2, we found that cerebellar morphology was perturbed along the dorsal midline, accompanied by a sharp decrease in the number of differentiated neurons within the cerebellum. Met signaling-deficient embryos also exhibit reduced proliferation compared to control embryos. We found that Met signaling-deficient embryos failed to specify ptf1a -expressing VZ progenitor cells as well as VZ-derived Purkinje cells. While Met signaling-deficient embryos form a normal upper rhombic lip (URL), the URL-derived granule cells are reduced or lost in morphants. We also found that neuronal migration in the hindbrain is affected in Met signaling-deficient morphants, as the migration of facial branchiomotor neurons (FBMN) is incomplete. Lastly, we found that FBMN migration is abnormal in Met signaling morphants because of a loss of hgf signaling from the underlying endoderm. We demonstrated this by showing that casanova morphants, which lack endoderm formation, have FBMN migration defects, indicating that endoderm is required for FBMN migration. We were able to rescue FBMN migration in hgf morphants by grafting hgf-positive donor cells into the endoderm, demonstrating that hgf ligands from the endoderm signal to the FBMNs in the neuroectoderm for proper migration. Our work here uncovers new roles and mechanisms for Met signaling during zebrafish neurogenesis.