Abstract
Neuroblastoma (NB) is an embryonal malignancy derived from the abnormal differentiation of the sympathetic nervous system. The Anaplastic Lymphoma Kinase (ALK) gene is frequently altered in NB, through copy number alterations and activating mutations, and represents a predisposition in NB-genesis when mutated. Our previously published data suggested that ALK activating mutations may impair the differentiation potential of neural crest (NC) progenitor cells. Here, we demonstrated that the expression of the endogenous ALK gene starts at E10.5 in the developing sympathetic ganglia (SG). To decipher the impact of deregulated ALK signaling during embryogenesis on the formation and differentiation of sympathetic neuroblasts, Sox10-Cre;LSL-ALK-F1174L embryos were produced to restrict the expression of the human ALK-F1174L transgene to migrating NC cells (NCCs). First, ALK-F1174L mediated an embryonic lethality at mid-gestation and an enlargement of SG with a disorganized architecture in Sox10-Cre;LSL-ALK-F1174L embryos at E10.5 and E11.5. Second, early sympathetic differentiation was severely impaired in Sox10-Cre;LSL-ALK-F1174L embryos. Indeed, their SG displayed a marked increase in the proportion of NCCs and a decrease of sympathetic neuroblasts at both embryonic stages. Third, neuronal and noradrenergic differentiations were blocked in Sox10-Cre;LSL-ALK-F1174L SG, as a reduced proportion of Phox2b+ sympathoblasts expressed βIII-tubulin and almost none were Tyrosine Hydroxylase (TH) positive. Finally, at E10.5, ALK-F1174L mediated an important increase in the proliferation of Phox2b+ progenitors, affecting the transient cell cycle exit observed in normal SG at this embryonic stage. Altogether, we report for the first time that the expression of the human ALK-F1174L mutation in NCCs during embryonic development profoundly disturbs early sympathetic progenitor differentiation, in addition to increasing their proliferation, both mechanisms being potential crucial events in NB oncogenesis.
Highlights
Neuroblastoma (NB) is a pediatric malignancy of the sympathetic nervous system (SNS) which may arise in the adrenal medulla (47%) or along the entire sympathetic chain (53%) [1, 2]
Due to the early embryonic lethality, we focused our analysis of the impact of Anaplastic Lymphoma Kinase (ALK)-F1174L expression in neural crest cells (NCCs) on the development and differentiation of the sympathetic chain, as the initial structure of the adrenal medulla appears at E12.5
We studied the involvement of deregulated ALK signaling on sympathetic ganglia formation and neuroblast differentiation during early embryonic development
Summary
Neuroblastoma (NB) is a pediatric malignancy of the sympathetic nervous system (SNS) which may arise in the adrenal medulla (47%) or along the entire sympathetic chain (53%) [1, 2]. The transcription factor (TF) Sox is expressed from ∼E9 in trunk migrating NCCs where it mediates their survival, aids in the maintenance of multipotency and inhibits neuronal differentiation [6]. NCCs of the sympathetic lineage follow a ventrolateral path to reach the vicinity of the dorsal aorta where bone morphogenetic proteins (BMPs) induce sympathetic neuron differentiation [5]. This involves the expression of various TFs, including Paired-like homeobox 2a/b (Phox2a/b), Achaetescute family BHLH transcription factor 1 (Ascl1), Insulinomaassociated 1 (Insm1), heart and neural crest derivatives expressed protein 2 (Hand2), and gata binding protein 3 (Gata3), acting as a network controlling the differentiation and specification of the NCCs into noradrenergic neurons [7]. The absence of even a single member of the TF network can lead to deregulation in sympathetic neuroblast proliferation, survival and/or noradrenergic differentiation [7]
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