1G-道場1-1
Post-translational modification of FOXP1 in brain development and ASD
臼井 紀好1，Araujo Daniel1，Co Marissa1，Harper Matthew1，鳥海 和也1,2，Tucker Haley3，Konopka Genevieve1
1テキサス大学サウスウエスタン・神経科学，2都医研・精神行動医学・統失PJ，3テキサス大学オースティン・分子遺伝微生物
Mutations in the gene encoding the transcription factor forkhead box P1（FOXP1）result in brain developmental abnormalities and developmental disorders such as autism spectrum disorders（ASD）and intellectual disability（ID）. However, the molecular mechanisms regulating FOXP1 function during human brain development and how disruption to these functions leads to developmental disorders are largely unknown. Our previous work has demonstrated that sumoylation of the related transcription factor FOXP2 is an important post-translational modification that regulates FOXP2 function and ultimately affects cerebellar development and related behaviors. We therefore assessed whether sumoylation of FOXP1 might similarly regulate its function in the brain. Here, we demonstrate that FOXP1 is sumoylated during brain development, and this modification peaks during embryonic brain development, at the time points relevant to genetic pathways implicated in ASD. The site of FOXP1 sumoylation at K636 is evolutionally conserved from mouse to human. We demonstrate that SUMO-1/2 and PIAS2/3 are the SUMO proteins and E3 SUMO ligases carrying out sumoylation of FOXP1. We further show a requirement for sumoylation of FOXP1 in neuronal development, in particular during embryonic brain development. Together, these data highlight one of the molecular mechanisms regulating the role of an ASD-relevant gene, FOXP1, during brain development. | | 1G-道場1-2
LOTUSはNogoにより誘起されるPirBの軸索伸長阻害を抑制する
栗原 裕司，竹居 光太郎
横浜市立大学 大学院 生命医科学研究科 生体機能医科学研究室
Axonal growth inhibitors such as Nogo proteins, myelin-associated glycoprotein（MAG）and oligodendrocyte myelin glycoprotein（OMgp）commonly bind to both receptors of Nogo receptor-1（NgR1）and paired immunoglobulin-like receptor B（PirB）, leading to enormous restriction of functional recovery after damage to the adult central nervous system. We have identified lateral olfactory tract usher substance（LOTUS）as a novel molecule that functions in axonal bundle formation by antagonizing NgR1. In this study, we found that LOTUS interacted not only with NgR1 but also with PirB. Overexpression of LOTUS with PirB in COS7 cells blocked the binding of Nogo66, which is the functional domain of NogoA, to PirB. Soluble form of LOTUS suppressed Nogo66-induced growth cone collapse in cultured dorsal root ganglion neurons and Nogo66-induced nerite outgrowth inhibition in cultured cerebellar granule neurons from ngr1-deficient mice. These results suggest that LOTUS functions as an antagonist for PirB. In therapeutic approaches for injured or degenerative brains, LOTUS may help to promote neuronal regeneration. |
