The Independent Probabilistic Firing of Transcription Factors: A Paradigm for Clonal Variability in the Zebrafish Retina

Abstract

SummaryEarly retinal progenitor cells (RPCs) in vertebrates produce lineages that vary greatly both in terms of cell number and fate composition, yet how this variability is achieved remains unknown. One possibility is that these RPCs are individually distinct and that each gives rise to a unique lineage. Another is that stochastic mechanisms play upon the determinative machinery of equipotent early RPCs to drive clonal variability. Here we show that a simple model, based on the independent firing of key fate-influencing transcription factors, can quantitatively account for the intrinsic clonal variance in the zebrafish retina and predict the distributions of neuronal cell types in clones where one or more of these fates are made unavailable.

Timing temporal transitions during brain development

“…Quantitative modeling of vertebrate retinal clones has argued that although expression of fate determinants in an individual RPCs may be stochastic, at the tissue-level early-fate determinant expression is biased to precede late-fate determinant expression, which can account for the known birth order and number of retinal cell types [32]. This raises the question of how fate determinant expression is biased through time?…”

Enhancer priming enables fast and sustained transcriptional responses to Notch signaling

“…For example, in cells exposed to estrogen, response times for transcription activation were highly variable and there was no coherent cycling between active and inactive states (Fritzsch et al 2018). Stochastic transcriptional behaviour is of key importance in several developmental decisions, such as differentiation of photoreceptors in the Drosophila eye (Wernet et al 2006), hematopoietic cell differentiation in mouse cells (Chang et al 2008;Ng et al 2018) or during neuronal differentiation in the zebrafish retina (Boije et al 2015). But while an attractive feature for promoting heterogeneity, inherent variability in responses could be extremely disruptive in developmental processes where the coordinated response of many cells is required to pattern specific structures.…”

Zinc finger gene nolz1 regulates the formation of retinal progenitor cells and suppresses the Lim3/Lhx3 phenotype of retinal bipolar cells in chicken retina

“…Photoreceptors and horizontal cells share and are derived from the same progenitor (Suzuki et al, 2013;Blixt and Hallb€ o€ ok, 2016), which expresses low levels of Lim1 (Boije et al, 2015). Photoreceptors and horizontal cells share and are derived from the same progenitor (Suzuki et al, 2013;Blixt and Hallb€ o€ ok, 2016), which expresses low levels of Lim1 (Boije et al, 2015).…”

“…The transcription factors Isl1, Lim1, and Lim3 are expressed in the developing retina and they regulate retinal neuron differentiation and identity. Photoreceptors and horizontal cells share and are derived from the same progenitor (Suzuki et al, 2013;Blixt and Hallb€ o€ ok, 2016), which expresses low levels of Lim1 (Boije et al, 2015). Lim1 expression increases in cells that will form horizontal cells and contributes to the specification of horizontal cells (Poche et al, 2007;Suga et al, 2009;Boije et al, 2015).…”

“…Photoreceptors and horizontal cells share and are derived from the same progenitor (Suzuki et al, 2013;Blixt and Hallb€ o€ ok, 2016), which expresses low levels of Lim1 (Boije et al, 2015). Lim1 expression increases in cells that will form horizontal cells and contributes to the specification of horizontal cells (Poche et al, 2007;Suga et al, 2009;Boije et al, 2015). Isl1 expression in horizontal cells determines the horizontal cell subtype by inhibiting Lim1 expression (Suga et al, 2009).…”