Integrated Patterning Programs During Drosophila Development Generate the Diversity of Neurons and Control Their Mature Properties

Abstract

During the approximately 5 days of Drosophila neurogenesis (late embryogenesis to the beginning of pupation), a limited number of neural stem cells produce approximately 200,000 neurons comprising hundreds of cell types. To build a functional nervous system, neuronal types need to be produced in the proper places, appropriate numbers, and correct times. We discuss how neural stem cells (neuroblasts) obtain so-called area codes for their positions in the nervous system (spatial patterning) and how they keep time to sequentially produce neurons with unique fates (temporal patterning). We focus on specific examples that demonstrate how a relatively simple patterning system (Notch) can be used reiteratively to generate different neuronal types. We also speculate on how different modes of temporal patterning that operate over short versus long time periods might be linked. We end by discussing how specification programs are integrated and lead to the terminal features of different neuronal types. Expected final online publication date for the Annual Review of Neuroscience, Volume 44 is July 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Gene regulatory networks controlling temporal patterning, neurogenesis, and cell-fate specification in mammalian retina

“…GRNs controlling retinal development are parallel, redundant, and complex. Much like in Drosophila (Doe, 2017;Rossi et al, 2021), cell states are maintained by networks of TFs that activate expression of TFs within cell-type-specific GRNs but often also repress expression of TFs in GRNs specific to other cell states, potentially mediating rapid and irreversible transitions between different stable transcriptional states. Regulatory relationships among individual cell-type-specific GRNs are temporally dynamic, often containing a mixture of positive-and negative-feedback Resource ll OPEN ACCESS loops, and reflect developmental changes in the timing of retinal neurogenesis.…”

“…The central nervous system (CNS) consists of many distinct cell types, which are generated in discrete though often overlapping temporal windows (Holguera and Desplan, 2018;Oberst et al, 2019;Paridaen and Huttner, 2014). In both vertebrates and invertebrates, temporal patterning is controlled intrinsically by dynamically regulated expression of transcription factors (TFs), which in turn regulate the ability of neural progenitors to proliferate and generate specific cell types (Cayouette et al, 2003;Doe, 2017;Rossi et al, 2021;Thor, 2017). Multiple individual TFs control temporal patterning in both Drosophila (Bayraktar and Doe, 2013;Erclik et al, 2017;Konstantinides et al, 2021) and mammalian (Sagner et al, 2020;Telley et al, 2019) neural progenitors, and large-scale gene expression analysis of developing CNS has identified many other dynamically expressed TFs (Carter et al, 2018;La Manno et al, 2021;Tiklova ´et al, 2019).…”

Gene regulatory networks controlling temporal patterning, neurogenesis, and cell fate specification in the mammalian retina

“…We observe similarities between the retinal and other systems in both the general mechanisms and in the specific genes that control this process. For instance, much like in Drosophila, transcription factors that control these transitions act to both promote expression of genes specific to individual cell states while inhibiting expression of genes specific to earlier, later or alternative states (Doe, 2017;Rossi et al, 2021). Furthermore, several individual genes --including Nfia, Nfib, and Pou2f2 --are confirmed or predicted to control temporal patterning in both retina and spinal cord, (Sagner et al, 2020).…”

“…The central nervous system is highly complex, and consists of many functionally and molecularly distinct cell types, which are generated in discrete though often overlapping temporal windows (Holguera and Desplan, 2018;Oberst et al, 2019;Paridaen and Huttner, 2014). In both vertebrates and invertebrates, temporal patterning is controlled intrinsically, by dynamically regulated expression of transcription factors, which in turn regulate the ability of neural progenitors to proliferate and generate specific cell types (Cayouette et al, 2003;Doe, 2017;Rossi et al, 2021;Thor, 2017). Multiple individual transcription factors that control temporal patterning in both Drosophila (Bayraktar and Doe, 2013;Erclik et al, 2017;Konstantinides et al, 2021) and mammalian (Sagner et al, 2020;Telley et al, 2019) neural progenitors, and large-scale gene expression analysis of the developing brain has identified many other dynamically expressed transcription factors (Carter et al, 2018;Manno et al;Tiklová et al, 2019).…”

A comprehensive series of temporal transcription factors in the fly visual system

“…This supports the idea that tTF series with defined temporal windows, where tTFs count time and switch fate in response to a purely transcriptional network, can only operate in short-lived stem cells, like those in the Drosophila optic lobes that live for approximately 20 hours. On the other hand, gradients could be more adequate to count time in long-lived stem cells, such as the mouse radial glia that live for more than 5 days 58 .…”