Development of the basal hypothalamus through anisotropic growth

Abstract

The adult hypothalamus is subdivided into distinct domains: pre‐optic, anterior, tuberal and mammillary. Each domain harbours an array of neurones that act together to regulate homeostasis. The embryonic origins and the development of hypothalamic neurones, however, remain enigmatic. Here, we summarise recent studies in model organisms that challenge current views of hypothalamic development, which traditionally have attempted to map adult domains to correspondingly located embryonic domains. Instead, new studies indicate that hypothalamic neurones arise from progenitor cells that undergo anisotropic growth, expanding to a greater extent than other progenitors, and grow in different dimensions. We describe in particular how a multipotent Shh / Fgf10 ‐expressing progenitor population gives rise to progenitors throughout the basal hypothalamus that grow anisotropically and sequentially: first, a subset displaced rostrally give rise to anterior‐ventral/tuberal neuronal progenitors; then a subset displaced caudally give rise to mammillary neuronal progenitors; and, finally, a subset(s) displaced ventrally give rise to tuberal infundibular glial progenitors. As this occurs, stable populations of Shh +ive and Fgf10 +ive progenitors form. We describe current understanding of the mechanisms that induce Shh +ive /Fgf10 +ive progenitors and begin to direct their differentiation to anterior‐ventral/tuberal neuronal progenitors, mammillary neuronal progenitors and tuberal infundibular progenitors. Taken together, these studies suggest a new model for hypothalamic development that we term the “anisotropic growth model”. We discuss the implications of the model for understanding the origins of adult hypothalamic neurones.

Developmental Genes and Malformations in the Hypothalamus

“…Placzek and Briscoe ( 2005 ), Manning et al ( 2006 ), Fu et al ( 2019 ) and Placzek et al ( 2020 ) misinterpreted in our opinion Shh -expressing cells observed in midsagittal sections at the chicken rostral diencephalic ventral midline as an “anterior floor plate” (no doubt assuming wrongly that Shh is always a floor plate marker). Actually, these median cells correspond to the Shh -expressing basal acroterminal subdomain.…”

“…Actually, these median cells correspond to the Shh -expressing basal acroterminal subdomain. Placzek and collaborators (Fu et al, 2019 ; Placzek et al, 2020 ) seem to have assimilated this particular notion, but conjecture a mixture of columnar and prosomeric notions in the form of a novel “anisotropic model of basal hypothalamic development.” Why the model should attend only to basal development remains unclear. In general, these authors seem to imagine the whole hypothalamus as represented by its midline.…”

“…The anteroposterior (AP) patterning effects are interpreted as affecting the DV dimension of the hypothalamus within the columnar tradition (e.g., Kapsimali et al, 2004 ). There is also a novel hybrid model proposed by Placzek and collaborators (Fu et al, 2019 ; Placzek et al, 2020 ).…”

Conserved Genoarchitecture of the Basal Hypothalamus in Zebrafish Embryos

“…The zebrafish PRR exhibits a high degree of continuous neurogenesis (Grandel et al, 2006;Wang et al, 2012). This might cause the overgrowth of the tuberal PRR and the peculiar shape of the RTuV/TuV domain which could be explained through anisotropic growth (Fu et al, 2019) of tuberal regions as the PRR bulges outward. To account for its divergent phylogenetic status, we suggest for this brain region not to adopt the mammalian nomenclature but to refer to it as PRR.…”

Of mitogens and morphogens: modelling Sonic Hedgehog mechanisms in vertebrate development

“…Despite this, only recently has there been a clearer understanding of how Shh governs the development and growth of the hypothalamus. It has now been shown that, after acting as a morphogen to pattern the DV axis, Shh-expressing ventral hypothalamic progenitors produce progenitors that populate much of the basal hypothalamus through anisotropic growth [ 49 ] (reviewed in [ 88 ]). The key insight from this work is that hypothalamic progenitor cells concurrently specify as they grow and migrate anisotropically.…”