mSEL‐1L is a highly conserved ER‐resident type I protein, involved in the degradation of misfolded peptides through the ubiquitin–proteasome system (UPS), a pathway known to control the plasticity of the vascular smooth muscle cells (VSMC) phenotype and survival. In this article, we demonstrate that mSEL‐1L deficiency interferes with the murine embryonic vascular network, showing particular irregularities in the intracranic and intersomitic neurovascular units and in the cerebral capillary microcirculation. During murine embryogenesis, mSEL‐1L is expressed in cerebral areas known to harbor progenitor neural cells, while in the adult brain the protein is specifically restricted to the stem cell niches, co‐localizing with Sox2 and Nestin. Null mice are characterized by important defects in the development of telenchephalic regions, revealing conspicuous aberration in neural stem cell lineage commitment. Moreover, mSEL‐1L depletion in vitro and in vivo appears to affect the harmonic differentiation of the NSCs, by negatively influencing the corticogenesis processes. Overall, the data presented suggests that the drastic phenotypic characteristics exhibited in mSEL‐1L null mice can, in part, be explained by the negative influence it plays on Notch1 signaling pathway. mSEL‐1L depletion in vitro and in vivo appears to affect the harmonic differentiation of the NSCs, by negatively influencing the corticogenesis processes. The data presented suggests that the drastic phenotypic characteristics exhibited in mSEL‐1L null mice can, in part, be explained by the negative influence it plays on Notch1 signaling pathway.