Haldipur Parthiv, Gillies Gwendolyn S, Janson Olivia K, Chizhikov Victor V, Mithal Divakar S, Miller Richard J, Millen Kathleen J
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States.
Department of Anatomy and Neurobiology, University of Tennessee Health Sciences Center, Memphis, United States.
Elife. 2014 Dec 16;3:e03962. doi: 10.7554/eLife.03962.
Loss of Foxc1 is associated with Dandy-Walker malformation, the most common human cerebellar malformation characterized by cerebellar hypoplasia and an enlarged posterior fossa and fourth ventricle. Although expressed in the mouse posterior fossa mesenchyme, loss of Foxc1 non-autonomously induces a rapid and devastating decrease in embryonic cerebellar ventricular zone radial glial proliferation and concurrent increase in cerebellar neuronal differentiation. Subsequent migration of cerebellar neurons is disrupted, associated with disordered radial glial morphology. In vitro, SDF1α, a direct Foxc1 target also expressed in the head mesenchyme, acts as a cerebellar radial glial mitogen and a chemoattractant for nascent Purkinje cells. Its receptor, Cxcr4, is expressed in cerebellar radial glial cells and conditional Cxcr4 ablation with Nes-Cre mimics the Foxc1-/- cerebellar phenotype. SDF1α also rescues the Foxc1-/- phenotype. Our data emphasizes that the head mesenchyme exerts a considerable influence on early embryonic brain development and its disruption contributes to neurodevelopmental disorders in humans.
Foxc1缺失与Dandy-Walker畸形相关，这是最常见的人类小脑畸形，其特征为小脑发育不全、后颅窝和第四脑室扩大。尽管Foxc1在小鼠后颅窝间充质中表达，但其缺失会非自主性地导致胚胎小脑室管膜区放射状胶质细胞增殖迅速且严重减少，同时小脑神经元分化增加。随后小脑神经元的迁移受到破坏，这与放射状胶质细胞形态紊乱有关。在体外，SDF1α是Foxc1的直接靶点，也在头部间充质中表达，它作为小脑放射状胶质细胞的促有丝分裂原和新生浦肯野细胞的趋化因子。其受体Cxcr4在小脑放射状胶质细胞中表达，用Nes-Cre进行条件性Cxcr4缺失可模拟Foxc1-/-小鼠的小脑表型。SDF1α也能挽救Foxc1-/-小鼠的表型。我们的数据强调，头部间充质对早期胚胎脑发育有相当大的影响，其破坏会导致人类神经发育障碍。
