Fig. 7: DENND5A-related DEE disease model.

a Under healthy developmental circumstances, apical progenitors are able to obtain a spindle orientation parallel to the apical ventricular surface. This allows both daughter cells to receive equal exposure to the stem and progenitor cell niche as well as inherit equal proportions of apical determinants, such as MUPP1 and PALS1, producing two identical apical progenitors after mitosis. The expansion of the progenitor pool early in brain development allows for an ideal production of neurons from diverse lineages and contributes to healthy brain development. b In the presence of biallelic pathogenic DENND5A variants, apical progenitors increasingly divide with a spindle angle perpendicular to the ventricular surface. This scenario only allows for one daughter cell to receive signaling molecules from the stem and progenitor cell niche and to inherit apical determinants, and the more basal daughter cell becomes either a basal progenitor or an immature neuron. Increased asymmetric cell division of apical neural progenitors during early development reduces the number of progenitors available for neurogenesis, resulting in a decreased overall number and diversity of neurons that contribute to microcephaly. This may contribute to abnormal neuronal connectivity, resulting in seizures that further adversely affect development, leading to DEE.