Antagonistic role of the BTB-zinc finger transcription factors Chinmo and Broad-Complex in the juvenile/pupal transition and in growth control

Abstract

During development, the growing organism transits through a series of temporally regulated morphological stages to generate the adult form. In humans, for example, development progresses from childhood through to puberty and then to adulthood, when sexual maturity is attained. Similarly, in holometabolous insects, immature juveniles transit to the adult form through an intermediate pupal stage when larval tissues are eliminated and the imaginal progenitor cells form the adult structures. The identity of the larval, pupal and adult stages depends on the sequential expression of the transcription factors chinmo, Br-C and E93. However, how these transcription factors determine temporal identity in developing tissues is poorly understood. Here we report on the role of the larval specifier chinmo in larval and adult progenitor cells during fly development. Interestingly, chinmo promotes growth in larval and imaginal tissues in a Br-C-independent and -dependent manner, respectively. In addition, we found that the absence of chinmo during metamorphosis is critical for proper adult differentiation. Importantly, we also provide evidence that, in contrast to the well-known role of chinmo as a pro-oncogene, Br-C and E93 act as tumour suppressors. Finally, we reveal that the function of chinmo as a juvenile specifier is conserved in hemimetabolous insects as its homolog has a similar role in Blatella germanica. Taken together, our results suggest that the sequential expression of the transcription factors Chinmo, Br-C and E93 during larva, pupa an adult respectively, coordinate the formation of the different organs that constitute the adut organism.

E93 controls adult differentiation by repressingbroadinDrosophila

“…The repression exerted by Br on early-larval enhancers and its role in terminating the juvenile developmental program, consequently inducing a permissive state for differentiation in wing cells, holds significance not only for developmental progression but also bears crucial implications for regeneration and tumor progression. Our findings, along with others (11, 22), strongly indicate that the regenerative capacity of damaged wing larval cells is contingent upon an environment lacking Br, thereby sustaining wing cells in a differentiation-refractory state. Indeed, it has been demonstrated that the wg 1 enhancer is activated in wing disc cells upon tissue injury, contributing to wing regeneration (25, 37), and further, this enhancer is repressed by Br in a context of tissue damage (38).…”

“…Notably, this stage marks the transition of wing disc cells from a state refractory to differentiation to one permissive for differentiation. This transition is governed by the reciprocal repression between the larval specifier Chinmo and Br (10, 11, 22).…”

“…In this context, our findings unveil that the acquisition of enhancer competence for induction from mid-L3 stems from the increasing levels of ecdysone, which occurs when the larva attains the “critical weight” (CW) checkpoint - a developmental growth-related milestone marking the irreversible commitment to metamorphosis (36). Notably, the rise in ecdysone levels also triggers the transition from chinmo to br expression, delineating the cellular shift from a state of differentiation resistance to a state of differentiation permissiveness (10, 11, 22). Thus, the surge in ecdysone signaling post-CW exerts a dual effect: it instructs enhancer inducibility while simultaneously triggering br expression, thereby preventing the untimely activation of such enhancers.…”

“…These hormones temporally regulate the expression of a specific set of genes encoding conserved stage-identity transcription factors, collectively known as the Metamorphic Gene Network (MGN) (9). In the holometabolous insect Drosophila melanogaster , the MGN encompasses three temporal factors: Chronologically inappropriate morphogenesis (Chinmo) (10, 11) and Broad (Br) (12), both members of the bric-a-brac-tramtrack-broad family, and Ecdysone inducible protein 93F (E93), a helix-turn-helix protein (13, 14). The regulatory actions of ecdysone and JH, combined with the mutual repression among chinmo , br and E93 , ensure their precisely sequential expression throughout development (10, 11), enabling them to regulate the genetic programs governing the larval, pupal and adult stages, respectively.…”

The moulting arthropod: a complete genetic toolkit review

“…Recent studies have identified additional putative key components of this fate determination regulatory network (Truman & Riddiford, 2022;Chafino et al, 2023). Chronologically Inappropriate Morphogenesis (chinmo) gene, encoding a BTB/POZ transcription factor like Broad, was proposed instead to play the role of a larval master gene.…”