The matrix protein Tiggrin regulates plasmatocyte maturation in Drosophila larva

Abstract

The lymph gland (LG) is a major source of hematopoiesis during Drosophila development. In this tissue, prohemocytes differentiate into multiple lineages, including macrophage-like plasmatocytes, which comprise the vast majority of mature hemocytes. Previous studies have uncovered genetic pathways that regulate prohemocyte maintenance and some cell fate choices between hemocyte lineages. However, less is known about how the plasmatocyte pool of the LG is established and matures. Here, we report that Tiggrin, a matrix protein expressed in the LG, is a specific regulator of plasmatocyte maturation. Tiggrin mutants exhibit precocious maturation of plasmatocytes, whereas Tiggrin overexpression blocks this process, resulting in a buildup of intermediate progenitors (IPs) expressing prohemocyte and hemocyte markers. These IPs likely represent a transitory state in prohemocyte to plasmatocyte differentiation. We also found that overexpression of Wee1 kinase, which slows G 2 /M progression, results in a phenotype similar to Tiggrin overexpression, whereas String/Cdc25 expression phenocopies Tiggrin mutants. Further analysis revealed that Wee1 inhibits plasmatocyte maturation through upregulation of Tiggrin transcription. Our results elucidate connections between the extracellular matrix and cell cycle regulators in the regulation of hematopoiesis.

Differential activation of JAK-STAT signaling in blood cell progenitors reveals functional compartmentalization of theDrosophilalymph gland

“…Dg binds ECM proteins like Perlecan, whose mutation causes reduced lymph gland growth and premature differentiation of the progenitors in the primary lobes . Similarly, the ECM protein Tiggrin was found to control the progression of intermediate progenitors to mature plasmatocytes (Zhang and Cadigan, 2017). Grigorian et al (2011) also suggested that hemocytes digest only a small part of the ECM to facilitate their dispersal and most of the ECM is left intact during metamorphosis.…”

“…The general view is that these lobes essentially harbor progenitors as initially suggested by the higher expression of DE-cadherin and the lack of expression of mature blood cell markers (Jung et al, 2005). Yet only few studies on progenitor differentiation in the primary lobe report on phenotypes in the secondary lobes (Owusu-Ansah and , Dragojlovic-Munther and Martinez-Agosto, 2013, Khadilkar et al, 2017b, Hao and Jin, 2017, Zhang and Cadigan, 2017, Kulkarni et al, 2011, Benmimoun et al, 2015. These studies revealed that posterior lobes could also differentiate in genetic contexts where there is extensive premature differentiation in primary lobes, however a thorough analysis of the posterior LG lobes is lacking.…”

Drosophila as a Genetic Model for Hematopoiesis

“…Lymph glands that lack Tig are overall smaller than wild-type and without Tig, plasmatocyte differentiation occurs early within the primary and posterior lobes (Zhang et al 2014). Overexpression of Tig in Hml + cells does not alter crystal cell and lamellocyte formation, but it does inhibit P1 and Eater expression, and thus plasmatocyte maturation (Zhang and Cadigan 2017).…”

“…In addition to these phenotypes, extranumerary posterior lobes are seen in asrij mutant animals and ectopic PSC cells are present in the secondary lobes of jumu mutants (Kulkarni et al 2011; Khadilkar et al 2017). Premature differentiation is the most prominent defect observed in the posterior lobes in animals mutant for Tiggrin or upon wasp parasitization (Sorrentino et al 2002; Zhang and Cadigan 2017). These phenotypes indicate that the molecular mechanisms that regulate hemocyte differentiation within the primary and posterior lobes might be similar, although they are employed at distinct stages of development.…”

Regulation of Drosophila Hematopoiesis in Lymph Gland: From a Developmental Signaling Point of View

“…The ECM protein Tiggrin (Tig) has been identified as a downstream effector of Wg signaling [ 60 , 61 ]. In lymph glands, Wg signal inhibits the expression of Tig .…”