Regulation of MET by FOXP2, genes implicated in higher cognitive dysfunction and autism risk.

Autism spectrum disorder (ASD) is a highly heritable, behaviorally defined, heterogeneous disorder of unknown pathogenesis. Several genetic risk genes have been identified, including the gene encoding the receptor tyrosine kinase MET, which regulates neuronal differentiation and growth. An ASD-associated polymorphism disrupts MET gene transcription, and there are reduced levels of MET protein expression in the mature temporal cortex of subjects with ASD. To address the possible neurodevelopmental contribution of MET to ASD pathogenesis, we examined the expression and transcriptional regulation of MET by a transcription factor, FOXP2, which is implicated in regulation of cognition and language, two functions altered in ASD. MET mRNA expression in the midgestation human fetal cerebral cortex is strikingly restricted, localized to portions of the temporal and occipital lobes. Within the cortical plate of the temporal lobe, the pattern of MET expression is highly complementary to the expression pattern of FOXP2, suggesting the latter may play a role in repression of gene expression. Consistent with this, MET and FOXP2 also are reciprocally expressed by differentiating normal human neuronal progenitor cells (NHNPs) in vitro, leading us to assess whether FOXP2 transcriptionally regulates MET. Indeed, FOXP2 binds directly to the 5' regulatory region of MET, and overexpression of FOXP2 results in transcriptional repression of MET. The expression of MET in restricted human neocortical regions, and its regulation in part by FOXP2, is consistent with genetic evidence for MET contributing to ASD risk.

Pediatric genetic macular and choroidal diseases.

Genetic diseases of the macula and choroid have various inheritance patterns and varying degrees of impact on vision. Herein, we review the literature including most recent advances in the understanding of the genetics of these diseases. Although many of these disorders have limited treatment options, knowledge of inheritance patterns can aid in early detection and with close monitoring can help the ophthalmologist preserve as much vision as possible (for example with early treatment of choroidal neovascularization).

The autism risk genes MET and PLAUR differentially impact cortical development.

Candidate risk genes for autism spectrum disorder (ASD) have been identified, but the challenge of determining their contribution to pathogenesis remains. We previously identified two ASD risk genes encoding the receptor tyrosine kinase MET and the urokinase plasminogen activator receptor (PLAUR), which is thought to modulate availability of the MET ligand. We also reported a role for Met signaling in cortical interneuron development in vitro and a reduction of these neurons in uPAR (mouse ortholog of PLAUR) null mice, suggesting that disruption of either gene impacts cortical development similarly. Here, we modify this conclusion, reporting that interneuron numbers are unchanged in the neocortex of Met(fx/fx) / Dlx5/6(cre) mice, in which Met is ablated from cells arising from the ventral telencephalon (VTel). Consistent with this, Met transcript is not detected in the VTel during interneuron genesis and migration; furthermore, during the postnatal period of interneuron maturation, Met is co-expressed in glutamatergic projection neurons, but not interneurons. Low levels of Met protein are expressed in the VTel at E12.5 and E14.5, likely reflecting the arrival of Met containing corticofugal axons. Met expression, however, is induced in E12.5 VTel cells after 2 days in vitro, perhaps underlying discrepancies between observations in vitro and in Met(fx/fx) / Dlx5/6(cre) mice. We suggest that, in vivo, Met impacts the development of cortical projection neurons, whereas uPAR influences interneuron maturation. An altered balance between excitation and inhibition has been postulated as a biological mechanism for ASD; this imbalance could arise from different risk genes differentially affecting either or both elements.

Dynamic gene and protein expression patterns of the autism-associated met receptor tyrosine kinase in the developing mouse forebrain.

The establishment of appropriate neural circuitry depends on the coordination of multiple developmental events across space and time. These events include proliferation, migration, differentiation, and survival-all of which can be mediated by hepatocyte growth factor (HGF) signaling through the Met receptor tyrosine kinase. We previously found a functional promoter variant of the MET gene to be associated with autism spectrum disorder, suggesting that forebrain circuits governing social and emotional function may be especially vulnerable to developmental disruptions in HGF/Met signaling. However, little is known about the spatiotemporal distribution of Met expression in the forebrain during the development of such circuits. To advance our understanding of the neurodevelopmental influences of Met activation, we employed complementary Western blotting, in situ hybridization, and immunohistochemistry to comprehensively map Met transcript and protein expression throughout perinatal and postnatal development of the mouse forebrain. Our studies reveal complex and dynamic spatiotemporal patterns of expression during this period. Spatially, Met transcript is localized primarily to specific populations of projection neurons within the neocortex and in structures of the limbic system, including the amygdala, hippocampus, and septum. Met protein appears to be principally located in axon tracts. Temporally, peak expression of transcript and protein occurs during the second postnatal week. This period is characterized by extensive neurite outgrowth and synaptogenesis, supporting a role for the receptor in these processes. Collectively, these data suggest that Met signaling may be necessary for the appropriate wiring of forebrain circuits, with particular relevance to the social and emotional dimensions of behavior.