Low density lipoprotein receptor-related protein, megalin, is a multifunctional lipoproptein receptor expressed by absorptive epithelia for endocytosis of numerous ligands. Megalin is widely expressed during embryonic life and is essential for development of the nervous system as evidenced by severe forebrain abnormalities in megalin (−/−). Here, we investigated the influence of megalin deficiency on prenatal spinal cord development in mice. In contrast to wild-type mice, cells expressing Olig2 and NG2, that is, oligodendroglial precursor cells, are absent from embryonic stage E16 in megalin (−/−) mice. At the end of prenatal development, there is a failure in vertebral development, and the number of astrocytes are markedly reduced in megalin (−/−) mice. These findings indicate that megalin is essential in astro–oligodendroglial interactions during development of the spinal cord.