Retinoic acid induced-1 (Rai1) regulates craniofacial and brain development in Xenopus

Abstract

Retinoic acid induced-1 (RAI1) is an important yet understudied histone code reader that when mutated in humans results in Smith-Magenis syndrome (SMS), a neurobehavioral disorder accompanied by signature craniofacial abnormalities. Despite previous studies in mouse and human cell models, very little is known about the function of RAI1 during embryonic development. In the present study, we have turned to the model vertebrates Xenopus laevis and Xenopus tropicalis to better understand the developmental roles of Rai1. First we demonstrate that the Rai1 protein sequence is conserved in frogs, especially in known functional domains. By in situ hybridization we revealed expression of rai1 in the developing craniofacial tissues and the nervous system. Knockdown of Rai1 using antisense morpholinos resulted in defects in the developing brain and face. In particular, Rai1 morphants display midface hypoplasia and malformed mouth shape analogous to defects in humans with SMS. These craniofacial defects were accompanied with aberrant neural crest migration and reduction in the size of facial cartilage elements. Rai1 morphants also had defects in axon patterns and decreased forebrain ventricle size. Such brain defects correlated with a decrease in the neurotrophic factor, bdnf, and increased forebrain apoptosis. Our results emphasize a critical role of Rai1 for normal neural and craniofacial development, and further the current understanding of potential mechanisms that cause SMS.

Reversible developmental stasis in response to nutrient availability in theXenopus laevisCNS

“…3, Table 1). These data are consistent with other studies showing that tectal size is not correlated to body length or NF stage (Sharma and Cline, 2010;Tahir et al, 2014;Thompson and Cline, 2016). The decrease in brain size is not due to increased cell death (Fig.…”

Modeling Human Craniofacial Disorders in Xenopus

“…In Xenopus, Rai1 is also upregulated by RA treatment. It is expressed in the neural plate at early stages of development, and in the pharyngeal arches, the otic vesicle and the developing central nervous system at later stages of development [84]. Morpholino-mediated knockdown of Rai1 resulted in dose-dependent alterations in head and body axis development.…”

Olfactory Mucosa Mesenchymal Stem Cells and Biomaterials: A New Combination to Regenerative Therapies after Peripheral Nerve Injury

“…Proteins like Dermcidin, retinoic acid induced 1 and cadherin 13 that contribute to cell cycle related events and play roles in neural diferentiation were also identiied. Dermcidin acts as a neural growth factor [95]; retinoic acid is involved in neurobehavioural disorders and plays a role in normal neural development [96] and Cadherin acts as a regulator of neural cell growth [97]. OM-MSCs were identiied as secreting high levels of the chemokine CXCL12 [98] that is known to be important in the promotion of endogenous myelinations [99].…”