Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
J Neurosci. 2011 Jan 26;31(4):1545-58. doi: 10.1523/JNEUROSCI.4467-10.2011.
NrCAM is a neural cell adhesion molecule of the L1 family that has been linked to autism spectrum disorders, a disease spectrum in which abnormal thalamocortical connectivity may contribute to visual processing defects. Here we show that NrCAM interaction with neuropilin-2 (Npn-2) is critical for semaphorin 3F (Sema3F)-induced guidance of thalamocortical axon subpopulations at the ventral telencephalon (VTe), an intermediate target for thalamic axon sorting. Genetic deletion of NrCAM or Npn-2 caused contingents of embryonic thalamic axons to misproject caudally in the VTe. The resultant thalamocortical map of NrCAM-null mutants showed striking mistargeting of motor and somatosensory thalamic axon contingents to the primary visual cortex, but retinogeniculate targeting and segregation were normal. NrCAM formed a molecular complex with Npn-2 in brain and neural cells, and was required for Sema3F-induced growth cone collapse in thalamic neuron cultures, consistent with a vital function for NrCAM in Sema3F-induced axon repulsion. NrCAM-null mice displayed reduced responses to visual evoked potentials recorded from layer IV in the binocular zone of primary visual cortex (V1), particularly when evoked from the ipsilateral eye, indicating abnormal visual acuity and ocularity. These results demonstrate that NrCAM is required for normal maturation of cortical visual acuity, and suggest that the aberrant projection of thalamic motor and somatosensory axons to the visual cortex in NrCAM-null mutant mice impairs cortical functions.
NrCAM 是 L1 家族的一种神经细胞粘附分子，与自闭症谱系障碍有关，这种疾病谱系中，异常的丘脑皮质连接可能导致视觉处理缺陷。在这里，我们表明 NrCAM 与神经纤毛蛋白-2（Npn-2）的相互作用对于半乳糖 3F（Sema3F）诱导丘脑皮质轴突亚群在腹侧端脑（VTe）的导向至关重要，VTe 是丘脑轴突分选的中间靶标。NrCAM 或 Npn-2 的基因缺失导致胚胎丘脑轴突的亚群在 VTe 中向后错位投射。NrCAM 缺失突变体的丘脑皮质图谱显示，运动和躯体感觉丘脑轴突亚群明显靶向初级视觉皮层的错误目标，但视网膜状突的靶向和分离正常。NrCAM 在大脑和神经细胞中与 Npn-2 形成分子复合物，并且是丘脑神经元培养物中 Sema3F 诱导的生长锥塌陷所必需的，这与 NrCAM 在 Sema3F 诱导的轴突排斥中的重要功能一致。NrCAM 缺失小鼠对视皮层（V1）的双眼区 IV 层记录的视觉诱发电位的反应降低，特别是当从同侧眼睛激发时，表明视觉敏锐度和眼性异常。这些结果表明 NrCAM 是正常皮层视觉敏锐度成熟所必需的，并表明 NrCAM 缺失突变体小鼠丘脑运动和躯体感觉轴突向视觉皮层的异常投射会损害皮层功能。
