Homeodomain protein Six4 prevents the generation of supernumerary Drosophila type II neuroblasts and premature differentiation of intermediate neural progenitors.

Yanjun Hou,Sijun Zhu,Marisa Connell,Claude Desplan,Rui Chen

doi:10.1371/journal.pgen.1009371

Yanjun Hou, Sijun Zhu + Show 3 more

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https://doi.org/10.1371/journal.pgen.1009371

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Journal: PLoS genetics	Publication Date: Feb 8, 2021
Citations: 13	License type: CC BY 4.0

Affiliation: SUNY Upstate Medical University

Abstract

In order to boost the number and diversity of neurons generated from neural stem cells, intermediate neural progenitors (INPs) need to maintain their homeostasis by avoiding both dedifferentiation and premature differentiation. Elucidating how INPs maintain homeostasis is critical for understanding the generation of brain complexity and various neurological diseases resulting from defects in INP development. Here we report that Six4 expressed in Drosophila type II neuroblast (NB) lineages prevents the generation of supernumerary type II NBs and premature differentiation of INPs. We show that loss of Six4 leads to supernumerary type II NBs likely due to dedifferentiation of immature INPs (imINPs). We provide data to further demonstrate that Six4 inhibits the expression and activity of PntP1 in imINPs in part by forming a trimeric complex with Earmuff and PntP1. Furthermore, knockdown of Six4 exacerbates the loss of INPs resulting from the loss of PntP1 by enhancing ectopic Prospero expression in imINPs, suggesting that Six4 is also required for preventing premature differentiation of INPs. Taken together, our work identified a novel transcription factor that likely plays important roles in maintaining INP homeostasis.

Highlights

Intermediate neural progenitor (INP) cells are fate-restricted progenitor cells generated from neural stem cells (NSCs)
Intermediate neural progenitors (INPs) are descendants of neural stem cells that can proliferate for a short term to amplify the number of nerve cells generated in the brain
We found that knockdown of Six4 in immature INPs (imINPs) with one copy of UAS-Six4RNAi driven by ermGAL4(II) alone or together with erm-GAL4(III) did not yield any phenotypes (S4A–S4C Fig), expression of two copies of UAS-Six4 RNAi driven by two copies of erm-GAL4(II) consistently led to generation of 1–2 extra type imINPs with erm-GAL4 (II) NBs per brain lobe with one lineage containing more than one type II NBs per brain lobe on average, which never occurred when two copies of UAS-mCherry RNAi was expressed (Fig 3A–3C” and 3F)

Summary

Introduction

Intermediate neural progenitor (INP) cells are fate-restricted progenitor cells generated from neural stem cells (NSCs). INPs serve to amplify the diversity and number of neurons generated from NSCs through transit proliferation, contributing to the generation of brain complexity [1,2]. To perform their function, INPs must overcome two challenges. One is to avoid dedifferentiation and reversion back to the NSC fate. Another is to avoid premature differentiation and cell cycle exit. Elucidating the cellular and molecular mechanisms regulating the self-renewal, differentiation, and dedifferentiation of INPs will provide insights into the generation of brain complexity, and help us understand cellular and molecular mechanisms of various neurodevelopmental disorders, such as microcephaly and other cortical malformations, as well as the development of brain tumors, which could originate from dedifferentiation of intermediate progenitors [3,4,5,6]

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