Hypoxic Stress Promotes Human Hypothalamic Hamartomas Pathogenesis through Regulating the TGFα-Mediated Slit2 and the Semaphorin Signaling Cascades in Hypothalamic Neuronal Progenitor Cells

Abstract

Abstract Hypothalamic hamartomas (HH), a developmental-deficient neurological disorder, is frequently accompanied with the hallmark symptoms of central precocious puberty (CPP) and epileptic (gelastic) seizures (GS), which results in patients’ cognitive abnormality as well as mental retardation. Molecular mechanisms underlying HH pathogenesis are still under investigation. In this study presented here, we collected cohorts of human HH tissue samples and explicitly investigated the role of hypoxic stress in HH initiation. Our finding reveals that hypoxic stress is a leading cause for HH pathology. Growing in an oxygen-deficient environment, embryonic neural progenitor cells isolated from hypothalamic region have to obtain nutritional ingredients including lactate and glutamate from hypoxic-associated glycolytic and glutaminolytic metabolisms, which is monitored by transforming growth factor (TGFα) signaling cascade. In turn, excessive productions of lactate and glutamate profoundly promotes hypothalamic neural progenitor cells (HNPCs)’ migration under hypoxic condition, which is accompanied by initiation of the TGFα-mediated Semaphorin cascade, but suppression of the TGFα-mediated Slit2 cascade. Intriguingly, TGFα and TGFβ affinity, but not TGFβ protein expressing dynamic, decides the signaling initiations of the two migration-associated cascades both in HH tissues as well as in HNPCs. Noteworthy, TGFβ restricts the release of TGFα from TGFα-TGFβ protein complex, and TGFβ participates in maintaining the spatial stability of this protein dimer in HNPCs subjected to hypoxic stress. Taken together, our findings demonstrate that hypoxic stress is a leading etiology for HH pathology, through manipulating the signaling transduction of the TGFα-mediated Slit2 cascade and the Semaphorin cascade in proliferating HNPCs susceptible to suffer from hypoxic stress over embryonic developmental period.