Neural crest metabolism: At the crossroads of development and disease

Abstract

The neural crest is a migratory stem cell population that contributes to various tissues and organs during vertebrate embryonic development. These cells possess remarkable developmental plasticity and give rise to many different cell types, including chondrocytes, osteocytes, peripheral neurons, glia, melanocytes, and smooth muscle cells. Although the genetic mechanisms underlying neural crest development have been extensively studied, many facets of this process remain unexplored. One key aspect of cellular physiology that has gained prominence in the context of embryonic development is metabolic regulation. Recent discoveries in neural crest biology suggest that metabolic regulation may play a central role in the formation, migration, and differentiation of these cells. This possibility is further supported by clinical studies that have demonstrated a high prevalence of neural crest anomalies in babies with congenital metabolic disorders. Here, we examine why neural crest development is prone to metabolic disruption and discuss how carbon metabolism regulates developmental processes like epithelial-to-mesenchymal transition (EMT) and cell migration. Finally, we explore how understanding neural crest metabolism may inform upon the etiology of several congenital birth defects.

Keywords: Aerobic glycolysis; Birth Defects; Carbon metabolism; Cell migration; Diabetes; EMT; Glycolysis; Neural crest; Neurocristopathies; Warburg Effect.

Figure 1.. Neural crest development and the genesis of metabolic neurocristopathies.

(A) The neural crest is migratory stem cell population that delaminates from the dorsal neural tube and migrates extensively throughout the embryo. Neural crest development requires drastic changes in cellular metabolism for the proper migration and differentiation of these cells. (B) Environmental or genetic factors may disrupt the metabolic transitions observed in neural crest cells, resulting in congenital disorders known as metabolic neurocristopathies. FASD: Fetal alcohol spectrum disorder, ROS: Reactive oxygen species.

Figure 2.. Glucose metabolism in differentiated versus tumor and stem cells.

(A) Oxidative Phosphorylation (OXPHOS) is the default cellular respiration mechanism for somatic cells under aerobic conditions. It results in 38 molecules of ATP per molecule of glucose. In the absence of oxygen, these cells engage in glycolysis to produce only 4 molecules of ATP. (B) Cancer and stem cell populations like the neural crest are highly glycolytic, even in the presence of oxygen. These cells display a metabolic adaptation known as the Warburg Effect and produce approximately 4 molecules of ATP per molecule of glucose.

Figure 3.. Control of neural crest delamination and migration by the Warburg effect.

High glycolytic flux in the pre-migratory neural crest promotes the interaction of YAP and TEAD, leading to the activation of genes that promote epithelial to mesenchymal transition (EMT). TAP/TEAD directly interact with tissue-specific enhancers to promote the EMT regulatory program (Adapted from Bhattacharya et al., 2020).

Figure 4.. Metabolic transitions during neural crest development.

(A) Early pre-migratory neural crest cells initially exhibit low levels of glycolysis and oxidative phosphorylation. As the cells become primed for epithelial to mesenchymal transition, they transition to a highly glycolytic state and undergo delamination and migration. After migration, neural crest cells differentiate and engage in oxidative phosphorylation (OXPHOS). (B) Estimated levels of glycolysis and oxidative phosphorylation during neural crest development. Neural crest cells undergo two main developmental transitions, when they transition from quiescent to glycolytic (1), and when they differentiate and display high levels of mitochondrial respiration (2). OXPHOS: Oxidative phosphorylation.