Shared roles for Scl and Lyl1 in murine platelet production and function

Abstract

The stem cell leukemia (Scl or Tal1) protein forms part of a multimeric transcription factor complex required for normal megakaryopoiesis. However, unlike other members of this complex such as Gata1, Fli1, and Runx1, mutations of Scl have not been observed as a cause of inherited thrombocytopenia. We postulated that functional redundancy with its closely related family member, lymphoblastic leukemia 1 (Lyl1) might explain this observation. To determine whether Lyl1 can substitute for Scl in megakaryopoiesis, we examined the platelet phenotype of mice lacking 1 or both factors in megakaryocytes. Conditional Scl knockout (KO) mice crossed with transgenic mice expressing Cre recombinase under the control of the mouse platelet factor 4 (Pf4) promoter generated megakaryocytes with markedly reduced but not absent Scl. These Pf4Sclc-KO mice had mild thrombocytopenia and subtle defects in platelet aggregation. However, Pf4Sclc-KO mice generated on an Lyl1-null background (double knockout [DKO] mice) had severe macrothrombocytopenia, abnormal megakaryocyte morphology, defective pro-platelet formation, and markedly impaired platelet aggregation. DKO megakaryocytes, but not single-knockout megakaryocytes, had reduced expression of Gata1, Fli1, Nfe2, and many other genes that cause inherited thrombocytopenia. These gene expression changes were significantly associated with shared Scl and Lyl1 E-box binding sites that were also enriched for Gata1, Ets, and Runx1 motifs. Thus, Scl and Lyl1 share functional roles in platelet production by regulating expression of partner proteins including Gata1. We propose that this functional redundancy provides one explanation for the absence of Scl and Lyl1 mutations in inherited thrombocytopenia.

Lyl-1 regulates primitive macrophages and microglia development

“…Recently, Lyl-1 was identified as a regulator of mesoderm cell fate 36 and of the maintenance of primitive erythroid progenitors. 37…”

“…The early expression of Lyl-1 in YS mesoderm (Giroux et al, 2007), where it cannot substitute for the mandatory function of its paralog Tal-1 for the generation of haematopoietic progenitors (Porcher et al, 2017), has already been established (reviewed in (Curtis et al, 2012)). More recently, Lyl-1 was also identified as a regulator of mesoderm cell fate in human induced pluripotent stem cells (iPSC) (Palpant et al, 2017), and its function in the maintenance of primitive erythroid progenitors has been described (Chiu et al, 2019). Parallel to Lyl-1 expression in the earliest wave of MΦ progenitor generation, our RNA-seq data now reveal Lyl-1 as an essential regulator in the specification of YS mesoderm to a haematopoietic fate since its invalidation affects major sets of genes involved in embryo patterning.…”

In Lyl1 −/− mice, adipose stem cell vascular niche impairment leads to premature development of fat tissues

“…Specifically, disruption of LYL1 activity in mice impairs the long‐term hematopoietic reconstitution capacity and maintenance of early T lineage progenitors, and partially blocks B lymphocyte differentiation 17,18 . More recently, Chiu et al demonstrated that Lyl1 can maintain primitive erythropoiesis and compensate for the loss of Scl (another bHLH family member) in megakaryopoiesis 19,20 . LYL1 is also required for the maturation and stabilization of endothelial adherens junctions in newly formed vessels 16,21 .…”

“…17,18 More recently, Chiu et al demonstrated that Lyl1 can maintain primitive erythropoiesis and compensate for the loss of Scl (another bHLH family member) in megakaryopoiesis. 19,20 LYL1 is also required for the maturation and stabilization of endothelial adherens junctions in newly formed vessels. 16,21 Consequently, blood vessels in the lung of young adult Lyl1 −/− mice cannot form a functional endothelial barrier, leading to vascular leakiness.…”

InLyl1-/-mice, adipose stem cell vascular niche impairment leads to premature development of fat tissues

“…demonstrated that Lyl1 can maintain primitive erythropoiesis and compensate for loss of Scl (a LYL1 co-member of bHLH family) in megakaryopoiesis [19,20]. LYL1 is also required for the maturation and stabilization of endothelial adherens junctions of newly formed vessels [16,21].…”