Generation of a Mouse Model to Study the Noonan Syndrome Gene Lztr1 in the Telencephalon.

Mary Jo Talley,Lisa A Ehrman,Carlos E Prada,Ronald R Waclaw,Nisha Shabbir,Diana Nardini

doi:10.3389/fcell.2021.673995

Abstract

The leucine zipper-like transcriptional regulator 1 (Lztr1) is a BTB-Kelch domain protein involved in RAS/MAPK pathway regulation. Mutations in LZTR1 are associated with cancers and Noonan syndrome, the most common RASopathy. The expression and function of Lztr1 in the developing brain remains poorly understood. Here we show that Lztr1 is expressed in distinct regions of the telencephalon, the most anterior region of the forebrain. Lztr1 expression was robust in the cortex, amygdala, hippocampus, and oligodendrocytes in the white matter. To gain insight into the impact of Lztr1 deficiency, we generated a conditional knockout (cKO) restricted to the telencephalon using Foxg1IREScre/+. Lztr1 cKOs are viable to postnatal stages and show reduced Lztr1 expression in the telencephalon. Interestingly, Lztr1 cKOs exhibit an increase in MAPK pathway activation in white matter regions and subsequently show an altered expression of stage-specific markers in the oligodendrocyte lineage with increased oligodendrocyte progenitor cells (OPCs) and decreased markers of oligodendrocyte differentiation. Moreover, Lztr1 cKOs also exhibit an increased expression of the astrocyte marker GFAP. These results highlight the generation of a new mouse model to study Lztr1 deficiency in the brain and reveal a novel role for Lztr1 in normal oligodendrocyte and astrocyte development in the telencephalon.

Highlights

LZTR1 was originally identified as one of the candidate genes deleted in some 22q11.2 deletion syndrome patients (Kurahashi et al, 1995)
Utilizing a conditional knockout strategy restricted to the telencephalon that results in postnatal viability, we have identified a novel role for Lztr1 in the normal generation of oligodendrocyte progenitor cells (OPCs) and the balanced establishment of oligodendrocyte and astrocyte differentiation markers
We found that Lztr1 deletion results in robust MAPK pathway activation and impacts the oligodendrocyte lineage

Summary

Introduction

LZTR1 was originally identified as one of the candidate genes deleted in some 22q11.2 deletion syndrome patients (Kurahashi et al, 1995). It is a unique member of the BTB-Kelch superfamily due to its localized expression to the golgi network via the C-terminal BTB/POZ domain (Nacak et al, 2006). Missense mutations in the Kelch domain that do not affect protein stability are associated with dominant NS, while loss-offunction or inactivating mutations are associated with biallelic recessive NS (Yamamoto et al, 2015; Johnston et al, 2018; Motta et al, 2019). While the NS clinical phenotype can be variable, Johnston et al (2018) showed examples of early lethality and cancers associated with the biallelic recessive mutations, which suggests that the LZTR1 loss-of-function or inactivating mutations might align with a more severe type of NS

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