The BMP antagonist gremlin 1 contributes to the development of cortical excitatory neurons, motor balance and fear responses.

Mari Ichinose,Jia Q Ng,Daniel L Worthley,Josephine A Wright,Paul Thomas,Krystyna A Gieniec,Atsushi Enomoto,Simon Koblar,Ryota Ando,Nobumi Suzuki,Susan L Woods,Laura Vrbanac,Martin Lewis,Hiroki Kobayashi,Tongtong Wang,Tamsin R M Lannagan

doi:10.1242/dev.195883

Abstract

ABSTRACTBone morphogenetic protein (BMP) signaling is required for early forebrain development and cortical formation. How the endogenous modulators of BMP signaling regulate the structural and functional maturation of the developing brain remains unclear. Here, we show that expression of the BMP antagonist Grem1 marks committed layer V and VI glutamatergic neurons in the embryonic mouse brain. Lineage tracing of Grem1-expressing cells in the embryonic brain was examined by administration of tamoxifen to pregnant Grem1creERT; Rosa26LSLTdtomato mice at 13.5 days post coitum (dpc), followed by collection of embryos later in gestation. In addition, at 14.5 dpc, bulk mRNA-seq analysis of differentially expressed transcripts between FACS-sorted Grem1-positive and -negative cells was performed. We also generated Emx1-cre-mediated Grem1 conditional knockout mice (Emx1-Cre;Grem1flox/flox) in which the Grem1 gene was deleted specifically in the dorsal telencephalon. Grem1Emx1cKO animals had reduced cortical thickness, especially layers V and VI, and impaired motor balance and fear sensitivity compared with littermate controls. This study has revealed new roles for Grem1 in the structural and functional maturation of the developing cortex.

Highlights

During development of the nervous system, bone morphogenetic protein (BMP) signaling has important roles in the promotion of dorsal identity, and the regulation of cell proliferation and differentiation
gremlin 1 (Grem1)-expressing cells are located in the dorsal telencephalon and give rise to deep-layer neocortical neurons Grem1 RNA was first detected by in situ hybridization (ISH) in the mouse dorsal telencephalon at 13.5 dpc and expression was maintained through embryonic development until 20.5 dpc (Fig. S1A)
Grem1 mRNA levels dramatically decreased after birth as determined by qRT-PCR analysis of total RNA isolated from mouse brain cortex at birth, postnatal day (P) 10 and 4 weeks post-birth (Fig. S1D)

Summary

Introduction

During development of the nervous system, bone morphogenetic protein (BMP) signaling has important roles in the promotion of dorsal identity, and the regulation of cell proliferation and differentiation. BMPs have been derived from the mesenchyme of the brain, such as meninges and endothelial cells (Imura et al, 2008; Choe and Pleasure, 2018) Both type I and II BMP receptors are expressed in the telencephalon during development, but this is restricted in adulthood to BmprII in the cortex and hippocampus and ActrIIA/IIB in the dentate gyrus (Söderström et al, 1996). Aside from this spatiotemporal regulation of receptors, the BMP signaling pathway is regulated by a family of secreted extracellular antagonists that directly bind to the BMP ligands to prevent interactions with BMP receptors both in development and disease (Ali and Brazil, 2014). Likewise the role of Grem in the normal adult CNS is unmapped territory to date, outside of previous work in the pathogenic state of glioma (Yan et al, 2014; Guan et al, 2017; Fu et al, 2018)

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