The Hippo Pathway Regulates Hematopoiesis in Drosophila melanogaster

Abstract

SUMMARY The Salvador-Warts-Hippo (Hippo) pathway is an evolutionarily conserved regulator of organ growth and cell fate. It performs these functions in epithelial and neural tissues of both insects and mammals, and in mammalian organs such as the liver and heart. Despite rapid advances in Hippo pathway research, a definitive role for this pathway in hematopoiesis has remained enigmatic. The hematopoietic compartments of Drosophila melanogaster and mammals possess several conserved features [1, 2]. D. melanogaster possess three types of hematopoietic cells that most closely resemble mammalian myeloid cells: plasmatocytes (macrophage-like cells), crystal cells (involved in wound healing) and lamellocytes (which encapsulate parasites). The proteins that control differentiation of these cells also control important blood lineage decisions in mammals [3–10]. Here, we define the Hippo pathway as a key mediator of hematopoiesis by showing that it controls differentiation and proliferation of the two major types of D. melanogaster blood cells, plasmatocytes and crystal cells. In animals lacking the downstream Hippo pathway kinase Warts, lymph gland cells overproliferated, differentiated prematurely and often adopted a mixed lineage fate. The Hippo pathway regulated crystal cell numbers by both cell autonomous and non-cell autonomous mechanisms. Yorkie and its partner transcription factor Scalloped were found to regulate transcription of the Runx family transcription factor, Lozenge, which is a key regulator of crystal cell fate. Further, Yorkie or Scalloped hyperactivation induced ectopic crystal cells in a non-cell autonomous, and Notch pathway-dependent fashion.

The RNA binding proteins RBM38 and DND1 are repressed in AML and have a novel function in APL differentiation

“…LATS2 is a member of the Hippo signaling pathway that is of outmost importance during development and early reports associated this pathway with hematopoiesis. [45] Consistently, we found that similar to p21 CIP1 also LATS2 mRNA expression is significantly decreased in NB4 RBM38 knockdown cells upon ATRA treatment (Additional file 3: Figure S2b). Thus, decreased LATS2 expression due to reduced RBM38 levels may also contribute to an immature myeloid phenotype.…”

Uncoupling of the Hippo and Rho pathways allows megakaryocytes to escape the tetraploid checkpoint

“…Previous reports have demonstrated the importance of the Hippo pathway in fly hematopoiesis. 25,26 It was also reported that key proteins of the Hippo pathway are expressed in mantle cell lymphoma. 27 Furthermore YAP, a key component of the Hippo pathway, is highly expressed in stem cells and decreases progressively during differentiation.…”

Hippo pathway deregulation: implications in the pathogenesis of haematological malignancies

“…Warts -knockout animals exhibit premature differentiation and overproliferation of lymph gland cells 43. Similarly, in Xenopus Mst1 -knockdown model, erythropoiesis, myelopoiesis and vasculogenesis were interrupted, but the stem cell or haematopoietic progenitor populations were maintained, suggesting that it is necessary to block Yap via Mst1 regulation during haematopoietic and endothelial cell differentiation 44…”