Generation and timing of graded responses to morphogen gradients

Abstract

Morphogen gradients are known to subdivide a naive cell field into distinct zones of gene expression. Here, we examine whether morphogens can also induce a graded response within such domains. To this end, we explore the role of the Dorsal protein nuclear gradient along the dorsoventral axis in defining the graded pattern of actomyosin constriction that initiates gastrulation in early Drosophila embryos. Two complementary mechanisms for graded accumulation of mRNAs of crucial zygotic Dorsal target genes were identified. First, activation of target-gene expression expands over time from the ventral-most region of high nuclear Dorsal to lateral regions, where the levels are lower, as a result of a Dorsal-dependent activation probability of transcription sites. Thus, sites that are activated earlier will exhibit more mRNA accumulation. Second, once the sites are activated, the rate of RNA Polymerase II loading is also dependent on Dorsal levels. Morphological restrictions require that translation of the graded mRNA be delayed until completion of embryonic cell formation. Such timing is achieved by large introns, which provide a delay in production of the mature mRNAs. Spatio-temporal regulation of key zygotic genes therefore shapes the pattern of gastrulation.

Dynamics of an incoherent feedforward loop drive ERK-dependent pattern formation in the earlyDrosophilaembryo

“…A unique feature of this circuit however is that the delay in hkb expression is dose-dependent, meaning that differences in signal amplitude are converted to differences in hkb dynamics and thus different byn responses (i.e., transient if hkb onset is fast, sustained if hkb onset is slow). Interestingly, a similar dose-dependent delay in transcriptional onset was recently shown for T48 downstream of the Dorsal gradient (Carmon et al 2021; Keller et al 2020). What is the mechanism underlying this delay in hkb onset?…”

“…Interestingly, a similar dose-dependent delay in transcriptional onset was recently shown for T48 downstream of the Dorsal gradient (Carmon et al 2021;Keller et al 2020). What is the mechanism underlying this delay in hkb onset?…”

DrosophilaFog/Cta and T48 pathways have overlapping and distinct contributions to mesoderm invagination

“…Both cta and t48 mutants reduced the width of the ventral-lateral multicellular myosin gradient, in addition to delaying the onset of accumulation. The timing of T48 and mist transcription onset initiates at nuclei along the ventral midline and progresses laterally (Carmon et al ., 2021). Furthermore, there is a gradient in the Pol II recruitment rate for each of these transcription units, which leads to graded activity.…”

“…Snail promotes apical myosin II recruitment and cell shape change, in part, by repressing the Bearded family of genes (Perez-Mockus et al ., 2017). Mist expression is regulated by Snail, and modulated by Twist and Dorsal, while Smog is maternally deposited into the embryo (Manning et al ., 2013; Kerridge et al ., 2016; Carmon et al ., 2021). Interestingly, genes downstream of Dorsal and Twist have a dynamic expression pattern – initiating expression at the ventral midline and starting later at more lateral positions (Lim et al ., 2017; Carmon et al ., 2021).…”

“…Mist expression is regulated by Snail, and modulated by Twist and Dorsal, while Smog is maternally deposited into the embryo (Manning et al ., 2013; Kerridge et al ., 2016; Carmon et al ., 2021). Interestingly, genes downstream of Dorsal and Twist have a dynamic expression pattern – initiating expression at the ventral midline and starting later at more lateral positions (Lim et al ., 2017; Carmon et al ., 2021). This ventral-lateral gradient of gene expression is thought to result in a multicellular gradient of T48 protein accumulation, Rho1 activation, and apical myosin II accumulation (Spahn and Reuter, 2013; Heer et al ., 2017; Lim et al ., 2017; Denk-Lobnig et al ., 2021).…”