Reduced Retinoic Acid Signaling During Gastrulation Induces Developmental Microcephaly.

Michal Gur,Liat Bendelac-Kapon,Abraham Fainsod,Yehuda Shabtai,Graciela Pillemer

doi:10.3389/fcell.2022.844619

Michal Gur, Liat Bendelac-Kapon + Show 3 more

Open Access

https://doi.org/10.3389/fcell.2022.844619

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Abstract

Retinoic acid (RA) is a central signaling molecule regulating multiple developmental decisions during embryogenesis. Excess RA induces head malformations, primarily by expansion of posterior brain structures at the expense of anterior head regions, i.e., hindbrain expansion. Despite this extensively studied RA teratogenic effect, a number of syndromes exhibiting microcephaly, such as DiGeorge, Vitamin A Deficiency, Fetal Alcohol Syndrome, and others, have been attributed to reduced RA signaling. This causative link suggests a requirement for RA signaling during normal head development in all these syndromes. To characterize this novel RA function, we studied the involvement of RA in the early events leading to head formation in Xenopus embryos. This effect was mapped to the earliest RA biosynthesis in the embryo within the gastrula Spemann-Mangold organizer. Head malformations were observed when reduced RA signaling was induced in the endogenous Spemann-Mangold organizer and in the ectopic organizer of twinned embryos. Two embryonic retinaldehyde dehydrogenases, ALDH1A2 (RALDH2) and ALDH1A3 (RALDH3) are initially expressed in the organizer and subsequently mark the trunk and the migrating leading edge mesendoderm, respectively. Gene-specific knockdowns and CRISPR/Cas9 targeting show that RALDH3 is a key enzyme involved in RA production required for head formation. These observations indicate that in addition to the teratogenic effect of excess RA on head development, RA signaling also has a positive and required regulatory role in the early formation of the head during gastrula stages. These results identify a novel RA activity that concurs with its proposed reduction in syndromes exhibiting microcephaly.

Highlights

Is a condition in which the brain fails to achieve its normal size (Abuelo, 2007; Toi et al, 2009; Mochida, 2009; Dyment et al, 2013; Faheem et al, 2015; Duerinckx and Abramowicz, 2018)
We have shown that many of the developmental malformations arising from embryonic alcohol exposure (EAE) are the result of reduced retinoic acid (RA) signaling (Yelin et al, 2005; Kot-Leibovich and Fainsod, 2009; Shabtai et al, 2018; Shabtai and Fainsod, 2018; Fainsod et al, 2020)
To support the requirement for RA signaling in the formation of the head, we reduced the endogenous RA levels by localized dorsal or ventral injection of mRNA encoding CYP26A1

Summary

Introduction

Is a condition in which the brain fails to achieve its normal size (Abuelo, 2007; Toi et al, 2009; Mochida, 2009; Dyment et al, 2013; Faheem et al, 2015; Duerinckx and Abramowicz, 2018). Besides the wide variation in head size in the human population (Natale and Rajagopalan, 2014), individuals with head circumferences (occipitofrontal) smaller by 3 standard deviations from the population mean (age, sex, and ethnicity matched), exhibit what is known as clinical microcephaly (Martini et al, 2018) These individuals encompass up to 0.1% of the human population and most of them suffer from significant intellectual disabilities (Abuelo, 2007). To elucidate the etiology of primary or developmental microcephaly we need to achieve a better understanding of the signals and processes that regulate the induction, patterning, and differentiation of the rostral neuroectoderm and subsequently the forebrain in the embryo (Abuelo, 2007; Mochida, 2009; Toi et al, 2009; Dyment et al, 2013; Faheem et al, 2015; Duerinckx and Abramowicz, 2018) which in turn will affect the size of the head (Koyabu et al, 2014; Ranke et al, 2015; Martini et al, 2018). The leading edge mesendoderm (LEM)/prechordal mesoderm (PCM) cells migrate to the rostral region beneath the prospective cranial neuroectoderm, and at this position, they will perform their inductive and patterning functions (Kaneda and Motoki, 2012; Huang and Winklbauer, 2018)

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