Conserved Genoarchitecture of the Basal Hypothalamus in Zebrafish Embryos

Abstract

Analyses of genoarchitecture recently stimulated substantial revisions of anatomical models for the developing hypothalamus in mammalian and other vertebrate systems. The prosomeric model proposes the hypothalamus to be derived from the secondary prosencephalon, and to consist of alar and basal regions. The basal hypothalamus can further be subdivided into tuberal and mamillary regions, each with distinct subregions. Albeit being a widely used model system for neurodevelopmental studies, no detailed genoarchitectural maps exist for the zebrafish (Danio rerio) hypothalamus. Here, we compare expression domains of zebrafish genes, including arxa, shha, otpa, isl1, lhx5, nkx2.1, nkx2.2a, pax6, and dlx5a, the orthologs of which delimit specific subregions within the murine basal hypothalamus. We develop the highly conserved brain-specific homeobox (bsx) gene as a novel marker for genoarchitectural analysis of hypothalamic regions. Our comparison of gene expression patterns reveals that the genoarchitecture of the basal hypothalamus in zebrafish embryos 48 hours post fertilization is highly similar to mouse embryos at E13.5. We found the tuberal hypothalamus in zebrafish embryos to be relatively large and to comprise previously ill-defined regions around the posterior hypothalamic recess. The mamillary hypothalamus is smaller and concentrates to rather medial areas in proximity to the anterior end of the neural tube floor plate. Within the basal hypothalamus we identified longitudinal and transverse tuberal and mamillary subregions topologically equivalent to those previously described in other vertebrates. However, the hypothalamic diencephalic boundary region and the posterior tuberculum still provide a challenge. We applied the updated prosomeric model to the developing zebrafish hypothalamus to facilitate cross-species comparisons. Accordingly, we applied the mammalian nomenclature of hypothalamic organization to zebrafish and propose it to replace some controversial previous nomenclature.

Developmental Genes and Malformations in the Hypothalamus

“…The prosomeric model is uniquely consistent with the multitude of brain developmental gene expression patterns accrued during the last 40 years, which were meaningless within the columnar model. It can explain many neurogenetic, axonal navigational and patterning data, and applies in other vertebrates (Puelles, 1995 ; Croizier et al, 2014 ; Domínguez et al, 2014 , 2015 ; Santos-Durán et al, 2015 , 2016 , 2018 ; Nieuwenhuys and Puelles, 2016 ; Gonzalez et al, 2017 ; Schredelseker and Driever, 2020 ). Several recent monographs present structural and functional vertebrate neuroanatomy, including that of the human brain, based on the prosomeric model (Watson et al, 2010 ; Striedter, 2016 ; ten Donkelaar, 2018 , 2020 ; Schröder et al, 2020 ; Striedter and Northcutt, 2020 ).…”

“…The prosomeric model reveals a shared genoarchitectonic hypothalamic structure in amniotes and anamniotes (Shimogori et al, 2010 ; Diez-Roux et al, 2011 ; Moreno et al, 2012 ; Puelles et al, 2012 , 2013 ; Puelles, 2013 ; Domínguez et al, 2014 ; Morales-Delgado et al, 2014 ; Díaz et al, 2015 ; Ferran et al, 2015 ; Puelles and Rubenstein, 2015 ; Santos-Durán et al, 2015 , 2016 , 2018 ; Schredelseker and Driever, 2020 ). Affaticati et al ( 2015 ) and Yamamoto et al ( 2017 ) largely confirmed this shared molecular pattern in zebrafish but suggested an alternative vision of the preoptic domain.…”

“…During early development, the hypothalamic primordium in vertebrates subdivides molecularly along the prosomeric anteroposterior and dorsoventral dimensions, created by the intersection of the new limits several progenitor domains, each characterized by a differential gene expression code (Shimogori et al, 2010 ; Diez-Roux et al, 2011 ; Puelles et al, 2012 ; Domínguez et al, 2015 ; Ferran et al, 2015 ; Santos-Durán et al, 2015 , 2016 , 2018 ; Schredelseker and Driever, 2020 ). As mentioned above, the hypothalamus subdivides dorsoventrally into alar, basal, and floor longitudinal fields throughout its length; the dorsalmost alar subregion corresponds to the telencephalic evagination (which is thus by origin entirely alar, irrespective of its subsequent pallio-subpallial subdivision).…”

“…This pattern occurs across most basal PHy and THy, excepting secondary lack of Shh expression at part of the THy tuberal area and absence of Nkx2.1 at the retromamillary area (Puelles et al, 2012 ). Other molecular markers are restricted to distinct rostrocaudal prosomeres (PHy, THy, AT) and their dorsoventral basal subdivisions ( Figure 3B ; Moreno et al, 2012 ; Puelles et al, 2012 ; Domínguez et al, 2014 , 2015 ; Ferran et al, 2015 ; Santos-Durán et al, 2015 , 2018 ; Gonzalez et al, 2017 ; Schredelseker and Driever, 2020 ). We distinguish across the bi-neuromeric basal hypothalamus three dorsoventral (longitudinal) domains, a dorsal tuberal/retrotuberal area (Tu/RTu), an intermediate perimamillary/periretromamillary area (PM/PRM), and a ventral mamillary/retromamillary area (M/RM; Figure 3 ).…”

Topological atlas of the hypothalamus in adult rhesus monkey

“…1. See list of abbreviations for complete terms Puelles and Rubenstein 2003;Lauter et al 2013;Dominguez et al 2014Dominguez et al , 2015Nieuwenhuys and Puelles 2016;Puelles 2018;Schredelseker and Driever 2020). We applied the principles of the prosomeric model to a topological analysis of architectonic landmarks to trace adult hypothalamic nuclei to their likely developmental origin in rhesus monkeys, as summarized in Fig.…”