FIGURE 1.

Panel I: Specification and cell fate acquisition of the neural crest cells (NCCs). (A) NCCs and placode progenitor cells are localized adjacent to each other at the neural plate border. (B) When neural folds are brought together, the stiffened mesoderm underlying the cranial NCCs (red arrows) triggers NCC EMT and initiate NCC migration. (C) The migrating NCCs undergo a gradual process of cell fate acquisition, during which the NCCs pass through two main bifurcation points. The first separation leads to the split of sensory and autonomic/mesenchymal fates, and the second separation leads to the emergence of autonomic and mesenchymal fates. Placode progenitors are split from the common PPR into individual placodes to give rise to different sensory organs or cranial ganglia. (D) NCCs migration streams and placode separation are a result of the interaction between NCCs and placode cells (middle): NCCs are attracted by placode cells (green arrows), after their direct contact placode cells are repolarized and move away from the NCCs (orange arrows), in a process called contact inhibition locomotion (CIL). Due to their active directed cell migration (orange arrows, below), the individual placode territories are established and NCCs had along their stereotypical migratory pathways. (A–C) Upper row transversal view, lower row: dorsal view; (D) lateral view. Panel II: Cellular behavior during early craniofacial morphogenesis. (A) The cranial NCCs migrated into their respective destinations and proliferate generating facial ectomesenchyme. (B) The progeny of each cranial NCC occupies a 3D area referred to as the clonal envelope. NCCs undergo cell divisions in an oriented manner, the shapes of clonal envelopes reflect the anisotropic growth of the head. The mesenchymal condensations originate from the local ectomesenchyme and represent the blueprint for chondrocranium and future facial shape. Extensive cell proliferation in quite distant locations results in collective cell movement translocating the whole micro-domains. (C) The mesenchymal condensations start differentiating into cartilage, the chondrocytes undergo a series of polarized cell divisions resulting in surface expansion of the chondrocranium. (D) Polarized cell division of NCC-derived ectomesenchyme is controlled by Wnt/Planar cell polarity (PCP) pathway and its disruption leads to shorter and wider facial proportions. The Blue asterisk shows the relevant time point of the Wnt/PCP signaling effect – during the proliferation of ectomesenchyme (panel IIB). Panel III: Signaling centers establish facial geometry. (A) Signaling centers located in the developing brain instruct the formation of mesenchymal condensations from the ectomesenchyme. (B) Sonic hedgehog (Shh) from the floor plate induces the condensation leading to the formation of nasal septum as well some elements of the cranial base, while morphogenetic signals from the olfactory epithelium induce the formation of nasal capsule roof. (C) Removal of morphogenetic signals from distinct locations results in the absence or malformation of the respective cartilaginous structures.