Abstract:Neural progenitor cells alter their output over developmental time to generate different types of neurons and glia in the correct sequences and proportions. A number of 'temporal identity factors' that control transitions in progenitor competence have been identified, but the molecular mechanisms underlying their function remain unclear. Here, we asked how the transcription factor Casz1, the mammalian orthologue of Drosophila castor, regulates competence during retinal neurogenesis. We show that Casz1 is requi… Show more
“…Kr and Pdm orthologs have been identified in vertebrates. Looking for dual expression of Kr and Pdm orthologs in vertebrates may reveal a role in specifying temporal identity, similar to evidence for Hb and Cas TTFs having vertebrate orthologs that specify temporal identity [7,9,10,40].…”
Background: Spatial patterning specifies neural progenitor identity, with further diversity generated by temporal patterning within individual progenitor lineages. In vertebrates, these mechanisms generate "cardinal classes" of neurons that share a transcription factor identity and common morphology. In Drosophila, two cardinal classes are Even-skipped (Eve) + motor neurons projecting to dorsal longitudinal muscles, and Nkx6 + motor neurons projecting to ventral oblique muscles. Cross-repressive interactions prevent stable double-positive motor neurons. The Drosophila neuroblast 7-1 (NB7-1) lineage uses a temporal transcription factor cascade to generate five distinct Eve + motor neurons; the origin and development of Nkx6 + motor neurons remains unclear. Methods: We use a neuroblast specific Gal4 line, sparse labelling and molecular markers to identify an Nkx6 + VO motor neuron produced by the NB7-1 lineage. We use lineage analysis to birthdate the VO motor neuron to the Kr + Pdm + neuroblast temporal identity window. We use gain-and loss-of-function strategies to test the role of Kr + Pdm + temporal identity and the Nkx6 transcription factor in specifying VO neuron identity. Results: Lineage analysis identifies an Nkx6 + neuron born from the Kr + Pdm + temporal identity window in the NB7-1 lineage, resulting in alternation of cardinal motor neuron subtypes within this lineage (Eve>Nkx6 > Eve). Cooverexpression of Kr/Pdm generates ectopic VO motor neurons within the NB7-1 lineagethe first evidence that this TTF combination specifies neuronal identity. Moreover, the Kr/Pdm combination promotes Nkx6 expression, which itself is necessary and sufficient for motor neuron targeting to ventral oblique muscles, thereby revealing a molecular specification pathway from temporal patterning to cardinal transcription factor expression to motor neuron target selection. Conclusions: We show that one neuroblast lineage generates interleaved cardinal motor neurons fates; that the Kr/ Pdm TTFs form a novel temporal identity window that promotes expression of Nkx6; and that the Kr/Pdm > Nkx6 pathway is necessary and sufficient to promote VO motor neuron targeting to the correct ventral muscle group.
“…Kr and Pdm orthologs have been identified in vertebrates. Looking for dual expression of Kr and Pdm orthologs in vertebrates may reveal a role in specifying temporal identity, similar to evidence for Hb and Cas TTFs having vertebrate orthologs that specify temporal identity [7,9,10,40].…”
Background: Spatial patterning specifies neural progenitor identity, with further diversity generated by temporal patterning within individual progenitor lineages. In vertebrates, these mechanisms generate "cardinal classes" of neurons that share a transcription factor identity and common morphology. In Drosophila, two cardinal classes are Even-skipped (Eve) + motor neurons projecting to dorsal longitudinal muscles, and Nkx6 + motor neurons projecting to ventral oblique muscles. Cross-repressive interactions prevent stable double-positive motor neurons. The Drosophila neuroblast 7-1 (NB7-1) lineage uses a temporal transcription factor cascade to generate five distinct Eve + motor neurons; the origin and development of Nkx6 + motor neurons remains unclear. Methods: We use a neuroblast specific Gal4 line, sparse labelling and molecular markers to identify an Nkx6 + VO motor neuron produced by the NB7-1 lineage. We use lineage analysis to birthdate the VO motor neuron to the Kr + Pdm + neuroblast temporal identity window. We use gain-and loss-of-function strategies to test the role of Kr + Pdm + temporal identity and the Nkx6 transcription factor in specifying VO neuron identity. Results: Lineage analysis identifies an Nkx6 + neuron born from the Kr + Pdm + temporal identity window in the NB7-1 lineage, resulting in alternation of cardinal motor neuron subtypes within this lineage (Eve>Nkx6 > Eve). Cooverexpression of Kr/Pdm generates ectopic VO motor neurons within the NB7-1 lineagethe first evidence that this TTF combination specifies neuronal identity. Moreover, the Kr/Pdm combination promotes Nkx6 expression, which itself is necessary and sufficient for motor neuron targeting to ventral oblique muscles, thereby revealing a molecular specification pathway from temporal patterning to cardinal transcription factor expression to motor neuron target selection. Conclusions: We show that one neuroblast lineage generates interleaved cardinal motor neurons fates; that the Kr/ Pdm TTFs form a novel temporal identity window that promotes expression of Nkx6; and that the Kr/Pdm > Nkx6 pathway is necessary and sufficient to promote VO motor neuron targeting to the correct ventral muscle group.
“…Looking for dual expression of Kr and Pdm orthologs in vertebrates may reveal a role in specifying temporal identity, similar to evidence for Hb and Cas TTFs having vertebrate orthologs that specify temporal identity (Alsiö et al, 2013;Elliott et al, 2008;Mattar et al, 2015;Mattar et al, 2020).…”
Background: Spatial patterning specifies neural progenitor identity, with further diversity generated by temporal patterning within individual progenitor lineages. These mechanisms generate cardinal classes of motor neurons, sharing a transcription factor identity and common muscle group targets). In Drosophila , two cardinal classes are Even-skipped (Eve)+ motor neurons projecting to dorsal longitudinal muscles and Nkx6+ motor neurons projecting to ventral oblique muscles. The Drosophila neuroblast 7-1 (NB7-1) lineage generates distinct Eve+ motor neurons via the temporal transcription factor (TTF) cascade Hunchback (Hb)-Krüppel (Kr)-Pdm-Castor (Cas).
Methods: Here we use sparse labelling and molecular markers to identify a novel VO motor neuron subtype in the NB7-1 lineage, and birth-date this neuron to a Kr+ Pdm+ temporal identity window. We selectively drive overexpression of Kr and Pdm in the NB7-1 lineage, and assay the production and axonal targeting of ectopic VO neurons. We then use gain- and loss-of-function strategies to show that the identity and targeting specificity of the VO neuron is dependent on the transcription factor Nkx6.
Results: Here we show that a newly discovered Kr/Pdm temporal identity window gives rise to an Nkx6+ Eve- motor neuron projecting to ventral oblique muscles, resulting in alternation of cardinal motor neuron subtypes from a single progenitor (Eve>Nkx6>Eve). We show that co-overexpression of Kr/Pdm generates ectopic VO motor neurons within the NB7-1 lineage – the first evidence that this TTF combination specifies neuronal identity. Moreover, we show that the Kr/Pdm combination promotes Nkx6 expression, which itself is necessary and sufficient for ventral oblique muscle targeting, thereby linking temporal patterning to motor neuron synaptic target selection.
Conclusions: We show that one neuroblast lineage generates interleaved cardinal motor neurons fates; that the Kr/Pdm TTFs form a novel temporal identity window that promotes expression of Nkx6; and that the Kr/Pdm>Nkx6 pathway is necessary and sufficient to specify VO motor neuron identity and morphology.
“…Pseudotime ordering and machine-learning strategies of these single-cell data also revealed lists of more complex patterns of co-regulated genes expressed in early and late RPCs ( Clark et al, 2019 ). Lastly, evidence that Casz1 suppresses late gliogenesis by interacting with chromatin-modifying complexes provides a mechanism by which tTFs establish competence windows ( Mattar et al, 2020 preprint). Fig.…”
Section: Evidence Of Temporal Patterning In Mammalian Neural Progenitmentioning
The developing central nervous system (CNS) is particularly prone to malignant transformation, but the underlying mechanisms remain unresolved. However, periods of tumor susceptibility appear to correlate with windows of increased proliferation, which are often observed during embryonic and fetal stages and reflect stereotypical changes in the proliferative properties of neural progenitors. The temporal mechanisms underlying these proliferation patterns are still unclear in mammals. In Drosophila, two decades of work have revealed a network of sequentially expressed transcription factors and RNA-binding proteins that compose a neural progenitor-intrinsic temporal patterning system. Temporal patterning controls both the identity of the post-mitotic progeny of neural progenitors, according to the order in which they arose, and the proliferative properties of neural progenitors along development. In addition, in Drosophila, temporal patterning delineates early windows of cancer susceptibility and is aberrantly regulated in developmental tumors to govern cellular hierarchy as well as the metabolic and proliferative heterogeneity of tumor cells. Whereas recent studies have shown that similar genetic programs unfold during both fetal development and pediatric brain tumors, I discuss, in this Review, how the concept of temporal patterning that was pioneered in Drosophila could help to understand the mechanisms of initiation and progression of CNS tumors in children.
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