Retinoic Acid Signaling in Vertebrate Hindbrain Segmentation: Evolution and Diversification

Abstract

In metazoans, Hox genes are key drivers of morphogenesis. In chordates, they play important roles in patterning the antero-posterior (A-P) axis. A crucial aspect of their role in axial patterning is their collinear expression, a process thought to be linked to their response to major signaling pathways such as retinoic acid (RA) signaling. The amplification of Hox genes following major events of genome evolution can contribute to morphological diversity. In vertebrates, RA acts as a key regulator of the gene regulatory network (GRN) underlying hindbrain segmentation, which includes Hox genes. This review investigates how the RA signaling machinery has evolved and diversified and discusses its connection to the hindbrain GRN in relation to diversity. Using non-chordate and chordate deuterostome models, we explore aspects of ancient programs of axial patterning in an attempt to retrace the evolution of the vertebrate hindbrain GRN. In addition, we investigate how the RA signaling machinery has evolved in vertebrates and highlight key examples of regulatory diversification that may have influenced the GRN for hindbrain segmentation. Finally, we describe the value of using lamprey as a model for the early-diverged jawless vertebrate group, to investigate the elaboration of A-P patterning mechanisms in the vertebrate lineage.

Transcriptional Regulation and Implications for Controlling Hox Gene Expression

“…These nested domains of expression generate a combinatorial Hox code, which provides a molecular framework that serves as a key regulatory step in specifying regional identities and properties of tissues that serves as a key regulatory step in specifying regional identities and properties of tissues along the A-P axis. A wide variety of studies in different species and cell culture models have revealed that the nested domains of Hox expression along the A-P axis arise in part through the ability of Hox clusters to integrate and respond to opposing signaling gradients, such as those of Retinoic acid (RA), Fibroblast growth factors (Fgfs) and Wingless related integration sites (WNTs) [5,[17][18][19][20][21][22][23][24][25][26][27][28][29]. Hence, it is important to understand the regulatory mechanisms through which signaling pathways are able to coordinately control the precise patterns of the transcription of the clustered Hox genes required for their roles in specifying diverse morphologic features along the A-P axis.…”

Sea lamprey enlightens the origin of the coupling of retinoic acid signaling to vertebrate hindbrain segmentation

“…To investigate potential roles for RA signaling in hindbrain development of the sea lamprey ( Petromyzon marinus, Pm ), we first identified members of gene families predicted to encode components of the enzymatic machinery involved in synthesis (Aldh1a) and degradation (Cyp26) of retinoids associated with neural tube development in jawed vertebrates 26 . We identified three predicted Cyp26-like genes in the sea lamprey germline genome assembly (KPetmar1) 44 , 45 , Cyp26A1 , C yp26B1/C1a , and Cyp26B1/C1b , and two Aldh1a-like genes, Aldh1a1/a2a and Aldh1a1/a2b .…”

“…These markers have been used in previous studies 34 , 39 , 42 , 63 and provide a readout of the molecular regionalization that demarcates neuroepithelial segments. To assess the effect of these treatments on hindbrain segmentation, we performed cISH on the drug-treated embryos using probes for key genes involved in hindbrain patterning: a) otx and wnt1 mark subdivision of the forebrain and midbrain 26 ; b) krox20 and kreisler are segmental subdivision genes that mark the r3/r5 and r5/r6 territories, respectively 34 , 42 ; and c) hoxβ1 , hoxα2 , hoxα3, hoxζ4 are segmental identity genes each marking different groups of rhombomeres (Fig. 5a ) 42 .…”

“…This suggests that a direct regulatory link between RA signaling and Hox expression may be an ancient feature of the core GRN coupled to A-P patterning of the body axis in all chordates (Fig. 1a ) 26 .

Fig.

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“…During early embryogenesis, the hindbrain is transiently organized into segments (rhombomeres), which lays down a ground plan for regional patterning of neural differentiation, circuit formation and head development 14 , 26 , 34 . Hindbrain segmentation is regulated by a conserved GRN which can be visualized as a hierarchical series of regulatory modules that govern sequential steps of the cellular and developmental patterning process.…”