The autism risk genes MET and PLAUR differentially impact cortical development.
Mouse data show MET and PLAUR change different cortical cells, giving us two clear gene-to-behavior paths in autism.
01Research in Context
What this study did
Scientists bred mice that lack either the MET gene or the PLAUR gene.
They watched how each missing gene changed the growth of two kinds of brain cells in the cortex.
The team wanted to know if both genes hurt the same cells or if they act on different ones.
What they found
Missing MET mainly harmed projection neurons, the brain’s long-distance messengers.
Missing PLAUR mainly hurt interneurons, the brain’s brake pedals.
The result shows two separate roads that can both lead to the excite-inhibit mix-up seen in autism.
How this fits with other research
Stichter et al. (2009) and Liu et al. (2011) link the MTHFR 677T allele to more gaze avoidance and self-injury in kids with autism.
Those papers look at behavior, while Matson et al. (2011) looks at cells, so they do not clash; they simply zoom in on different parts of the same puzzle.
Huang et al. (2010) found another gene, RPP25, is also low in autism cortex, adding more proof that many genes can shape the same brain area.
Why it matters
When you read a genetic report, note which risk genes are listed. If MET shows up, think about excitatory balance and social output. If PLAUR shows up, think about inhibitory balance and self-regulation. You can then pick goals that match the likely brain pathway, such as social skills for MET or self-control games for PLAUR.
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02At a glance
03Original abstract
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.
Autism research : official journal of the International Society for Autism Research, 2011 · doi:10.1002/aur.172