Hox genes: Downstream “effectors” of retinoic acid signaling in vertebrate embryogenesis

Abstract

Summary One of the major regulatory challenges of animal development is to precisely coordinate in space and time the formation, specification, and patterning of cells that underlie elaboration of the basic body plan. How does the vertebrate plan for the nervous and hematopoietic systems, heart, limbs, digestive, and reproductive organs derive from seemingly similar population of cells? These systems are initially established and patterned along the anteroposterior axis (AP) by opposing signaling gradients that lead to the activation of gene regulatory networks involved in axial specification, including the Hox genes. The retinoid signaling pathway is one of the key signaling gradients coupled to the establishment of axial patterning. The nested domains of Hox gene expression, which provide a combinatorial code for axial patterning, arise in part through a differential response to retinoic acid (RA) diffusing from anabolic centers established within the embryo during development. Hence, Hox genes are important direct effectors of retinoid signaling in embryogenesis. This review focuses on describing current knowledge on the complex mechanisms and regulatory processes, which govern the response of Hox genes to RA in several tissue contexts including the nervous system during vertebrate development.

Retinoic acid organizes the vagus motor topographic map via spatiotemporal regulation of Hgf/Met signaling

“…We identify a critical role for RA signaling in mX neuron identity. RA is a well-established regulator of early rhombomeric A-P patterning in the hindbrain (Moens and Prince, 2002;Nolte et al, 2019) and, later, in the specification of motor neuron subtypes in the spinal cord (Sockanathan and Jessell, 1998;Sockanathan et al, 2003). RA signaling has also been proposed to provide positional information for topographic axon targeting in the olfactory and retinotopic maps (Login et al, 2015;Sen et al, 2005).…”

“…RA is a morphogen that controls A-P embryonic patterning, primarily through the transcriptional regulation of Hox genes (Nolte et al, 2019;Rhinn and Dolle, 2012). RA is produced in the paraxial mesoderm posterior to the hindbrain, and plays a crucial early (before 14 hpf) role in the A-P patterning of the hindbrain (Moens and Prince, 2002;Nolte et al, 2019), as well as in the patterning of spinal motor neurons (Diez del Corral et al, 2003;Novitch et al, 2003).…”

“…RA is a morphogen that controls A-P embryonic patterning, primarily through the transcriptional regulation of Hox genes (Nolte et al, 2019;Rhinn and Dolle, 2012). RA is produced in the paraxial mesoderm posterior to the hindbrain, and plays a crucial early (before 14 hpf) role in the A-P patterning of the hindbrain (Moens and Prince, 2002;Nolte et al, 2019), as well as in the patterning of spinal motor neurons (Diez del Corral et al, 2003;Novitch et al, 2003). Although RA can play a late (post-24 hpf) role in nervous system patterning in some contexts, such as in guiding enteric neural crest migration (Uribe et al, 2017), it is believed that its ability to specify A-P identity in the hindbrain is restricted to a critical window early in development (Begemann and Meyer, 2001).…”

Gsx2 is involved in specification of neurons in the inferior olivary nuclei from Ptf1a-expressing neuronal progenitors in zebrafish

“…hox genes function downstream of RA signals (reviewed in (Nolte et al, 2019)). Defects in the RA signal in zebrafish result in a strong reduction or absence of hoxb4a in the caudal hindbrain (Begemann et al, 2004;Begemann et al, 2001;Grandel et al, 2002).…”

Inter‐rhombomeric interactions reveal roles for fibroblast growth factors signaling in segmental regulation of EphA4 expression

“…9,31,[33][34][35] In the hindbrain GRN, fibroblast growth factor (FGF) and retinoid (RA) signaling, are two of the key signaling pathways that play important roles in setting up the initial patterns of expression of transcription factors, such as Krox20, Kreisler/MafB/valentine, vhnf1, Hoxa1, and Hoxb1, which regulate the formation and development of hindbrain segments. 1,7,22,32,[36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55] For example, in chick and zebrafish embryos the combined inputs from FGF3 and FGF8 signaling are required for establishing the correct identities of hindbrain segments through their inputs into expression of transcription factors such as Krox20, Kreisler/MafB/valentino, and Hoxb1. 39,41,50,54,55 RA and FGF signaling also control later steps in the progressive series of events associated with hindbrain segmentation.…”