Relaxin ligand/receptor systems in the developing teleost fish brain: Conserved features with mammals and a platform to address neuropeptide system functions

Abstract

The relaxins (RLNs) are a group of peptide hormone/neuromodulators that can regulate a wide range of physiological processes ranging from reproduction to brain function. All the family members have originated from a RLN3-like ancestor via different rounds of whole genome and gene specific duplications during vertebrate evolution. In mammals, including human, the divergence of the different family members and the emergence of new members led to the acquisition of specific functions for the various relaxin family peptide and associated receptor genes. In particular, in mammals, it was shown, that the role of RLN3 is correlated to the modulation of arousal, stress responses, emotion, social recognition, and other brain functions, positioning this gene/peptide as a potential therapeutic target for neuropsychiatric disorders. This review highlights the evolutionary conservation of relaxin family peptide and receptor gene expression and their associated brain neural circuits. In the zebrafish, the expression pattern of the different relaxin family members has specific features that are conserved in higher species, including a likely similar functional role for the ancestral RLN3-like gene. The use of different model organisms, particularly the zebrafish, to explore the diversification and conservation of relaxin family ligands and receptor systems, provides a relatively high-throughput platform to identify their specific conserved or differential neuromodulatory roles in higher species including human.

Keywords: griseum centrale; neuropsychiatric disorders; nucleus incertus; relaxins; stress response; zebrafish.

FIGURE 1

Schematic illustration of relaxin ligand and receptor expression patterns in the larval zebrafish brain. crhr1, corticotropin-releasing hormone type 1 receptor gene; ccl, ganglion cell layer; E, epiphysis; Hb, habenula; Hc, caudal hypothalamus; inl, inner cell layer; L, lens; NI, nucleus incertus; NIII, NIII cranial nerve nuclei; NV, NV cranial nerve nuclei; NVI, NVI cranial nerve nuclei; PAL, pallium; PAG, periaqueductal gray; PO, preoptic area; rln, relaxin; rln3a, relaxin peptide 3a gene; rln3b, relaxin peptide 3b gene; RN, raphe; rxfp1, relaxin family peptide type 1 receptor gene; rxfp3-2b, relaxin family peptide type 3 receptor 2b gene; rxfp3-3b, relaxin family peptide type 3 receptor 3b gene; TeO, optic tectum; TH, thalamus.

FIGURE 2

The connectivity pattern of the griseum centrale in zebrafish and the nucleus incertus in rat. AMY, amygdala; dHbL, dorsal habenula lateral part; dIPN, dorsal interpeduncular nucleus; GC, griseum centrale; HIP, hippocampus; HYP, hypothalamus; IPN, interpeduncular nucleus; nCX, neocortex; mHb, medial habenula; NI, nucleus incertus; PAL, pallium; RN, raphe nucleus; SNc, substantia nigra pars compacta.