Abstract
Recent studies indicate that many developing tissues modify glycolysis to favor lactate synthesis (Agathocleous et al., 2012; Bulusu et al., 2017; Gu et al., 2016; Oginuma et al., 2017; Sá et al., 2017; Wang et al., 2014; Zheng et al., 2016), but how this promotes development is unclear. Using forward and reverse genetics in zebrafish, we show that disrupting the glycolytic gene phosphoglycerate kinase-1 (pgk1) impairs Fgf-dependent development of hair cells and neurons in the otic vesicle and other neurons in the CNS/PNS. Fgf-MAPK signaling underperforms in pgk1- / - mutants even when Fgf is transiently overexpressed. Wild-type embryos treated with drugs that block synthesis or secretion of lactate mimic the pgk1- / - phenotype, whereas pgk1- / - mutants are rescued by treatment with exogenous lactate. Lactate treatment of wild-type embryos elevates expression of Etv5b/Erm even when Fgf signaling is blocked. However, lactate's ability to stimulate neurogenesis is reversed by blocking MAPK. Thus, lactate raises basal levels of MAPK and Etv5b (a critical effector of the Fgf pathway), rendering cells more responsive to dynamic changes in Fgf signaling required by many developing tissues.
Highlights
Development of the paired sensory organs of the head relies on critical contributions from cranial placodes
Hair cells are innervated by neurons of the statoacoustic ganglion (SAG), progenitors of which originate from the otic vesicle
Specification of SAG neuroblasts is initiated by localized expression of the bHLH factor Neurogenin1 (Ngn1) (Andermann et al, 2002; Korzh et al, 1998; Ma et al, 1998; Raft et al, 2007)
Summary
Development of the paired sensory organs of the head relies on critical contributions from cranial placodes. The otic placode initially forms a fluid filled cyst, the otic vesicle, which subsequently undergoes extensive proliferation and morphogenesis to produce a series of interconnected chambers containing sensory epithelia (Whitfield, 2015). Hair cell specification is initiated by expression of the bHLH factor Atonal Homolog 1 (Atoh1) (Bermingham et al, 1999; Chen et al, 2002; Millimaki et al, 2007; Raft et al, 2007; Woods et al, 2004). Specification of SAG neuroblasts is initiated by localized expression of the bHLH factor Neurogenin (Ngn1) (Andermann et al, 2002; Korzh et al, 1998; Ma et al, 1998; Raft et al, 2007). A subset of SAG neuroblasts delaminate from the otic vesicle to form ‘transit-amplifying’ progenitors that slowly cycle as they migrate to a position between the otic vesicle and hindbrain before completing differentiation and extending processes to hair cells and central targets in the brain (Alsina et al, 2004; Kantarci et al, 2016; Vemaraju et al, 2012)
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