The University of Queensland, Queensland Brain Institute, Brisbane, Australia.
Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia.
Elife. 2021 Apr 19;10:e61769. doi: 10.7554/eLife.61769.
The forebrain hemispheres are predominantly separated during embryogenesis by the interhemispheric fissure (IHF). Radial astroglia remodel the IHF to form a continuous substrate between the hemispheres for midline crossing of the corpus callosum (CC) and hippocampal commissure (HC). Deleted in colorectal carcinoma (DCC) and netrin 1 (NTN1) are molecules that have an evolutionarily conserved function in commissural axon guidance. The CC and HC are absent in and knockout mice, while other commissures are only partially affected, suggesting an additional aetiology in forebrain commissure formation. Here, we find that these molecules play a critical role in regulating astroglial development and IHF remodelling during CC and HC formation. Human subjects with mutations display disrupted IHF remodelling associated with CC and HC malformations. Thus, axon guidance molecules such as DCC and NTN1 first regulate the formation of a midline substrate for dorsal commissures prior to their role in regulating axonal growth and guidance across it.
大脑前半球在胚胎发生过程中主要通过大脑半球间裂（interhemispheric fissure，IHF）分隔。放射状星形胶质细胞重塑 IHF，在半球之间形成一个连续的基质，以允许胼胝体（corpus callosum，CC）和海马联合（hippocampal commissure，HC）的中线交叉。结直肠癌缺失基因（deleted in colorectal carcinoma，DCC）和轴突导向因子 1（netrin 1，NTN1）是在连合纤维轴突导向中具有进化保守功能的分子。和 基因敲除小鼠中 CC 和 HC 缺失，而其他连合纤维仅部分受影响，提示在大脑前连合形成中有额外的病因。在这里，我们发现这些分子在调节 CC 和 HC 形成过程中的星形胶质细胞发育和 IHF 重塑中发挥关键作用。携带 突变的人类受试者表现出 IHF 重塑紊乱，与 CC 和 HC 畸形有关。因此，轴突导向分子如 DCC 和 NTN1 首先调节背侧连合中线基质的形成，然后再调节其穿过中线的轴突生长和导向作用。
