Neuroblastoma (NB) is a childhood tumor that arises from the sympathoadrenal lineage.MYCNamplification is the most reliable marker for poor prognosis andMYCNoverexpression in embryonic mouse sympathetic ganglia results in NB-like tumors. MYCN cooperates with mutational activation of anaplastic lymphoma kinase (ALK), which promotes progression to NB, but the role of MYCN and ALK in tumorigenesis is still poorly understood. Here, we use chick sympathetic neuroblasts to examine the normal function ofMYCNandMYCin the control of neuroblast proliferation, as well as effects of overexpression ofMYCN,MYC, and activated ALK, alone and in combination. We demonstrate thatMYCis more strongly expressed thanMYCNduring neurogenesis and is important forin vitroneuroblast proliferation.MYCandMYCNoverexpression elicits increased proliferation but does not sustain neuroblast survival. Unexpectedly, long-term expression of activatedALKF1174Lleads to cell-cycle arrest and promotes differentiation and survival of postmitotic neurons.ALKF1174LinducesNEFM,RET, andVACHTand results in decreased expression of proapototic (BMF, BIM), adrenergic (TH), and cell-cycle genes (e.g.,CDC25A, CDK1). In contrast, neuroblast proliferation is maintained whenMYCNandALKF1174Lare coexpressed. ProliferatingMYCN/ALKF1174Lneuroblasts display a differentiated phenotype but differ fromALK-expressing neurons by the upregulation ofSKP2,CCNA2,E2F8, andDKC1. Inhibition of the ubiquitin ligase SKP2 (S-phase kinase-associated protein 2), which targets the CDK inhibitor p27 for degradation, reduces neuroblast proliferation, implicating SKP2 in the maintained proliferation ofMYCN/ALKF1174Lneuroblasts. Together, our results characterize MYCN/ALK cooperation leading to neuroblast proliferation and survival that may represent initial steps toward NB development.SIGNIFICANCE STATEMENTMYCN overexpression combined with activated anaplastic lymphoma kinase (ALK) is sufficient to induce neuroblastoma (NB) in mouse sympathoadrenal cells. To address cellular and molecular effects elicited by MYCN/ALK cooperation, we used cultures of chick sympathetic neuroblasts. We demonstrate thatMYCNincreases proliferation but not survival, whereas long-term expression ofALKF1174Lelicits cell-cycle exit, differentiation, and survival of postmitotic neurons. CombinedMYCN/ALKF1174Lexpression allows long-term proliferation and survival of neuroblasts with differentiated characteristics. In the presence ofALKF1174Lsignaling,MYCNinduces the expression of the ubiquitin ligase SKP2 (S-phase kinase-associated protein 2), which targets p27 for degradation and is also upregulated in high-risk NB. SKP2 inhibition supports a function for SKP2 in the maintained neuroblast proliferation downstream of MYCN/ALK, which may represent an early step toward tumorigenesis.