Sonic hedgehog lineage in the mouse hypothalamus: from progenitor domains to hypothalamic regions

Gonzalo Alvarez-Bolado,Sandra Blaess,Fabian A Paul

doi:10.1186/1749-8104-7-4

Abstract

BackgroundThe hypothalamus is a brain region with essential functions for homeostasis and energy metabolism, and alterations of its development can contribute to pathological conditions in the adult, like hypertension, diabetes or obesity. However, due to the anatomical complexity of the hypothalamus, its development is not well understood. Sonic hedgehog (Shh) is a key developmental regulator gene expressed in a dynamic pattern in hypothalamic progenitor cells. To obtain insight into hypothalamic organization, we used genetic inducible fate mapping (GIFM) to map the lineages derived from Shh-expressing progenitor domains onto the four rostrocaudally arranged hypothalamic regions: preoptic, anterior, tuberal and mammillary.ResultsShh-expressing progenitors labeled at an early stage (before embryonic day (E)9.5) contribute neurons and astrocytes to a large caudal area including the mammillary and posterior tuberal regions as well as tanycytes (specialized median eminence glia). Progenitors labeled at later stages (after E9.5) give rise to neurons and astrocytes of the entire tuberal region and in particular the ventromedial nucleus, but not to cells in the mammillary region and median eminence. At this stage, an additional Shh-expressing domain appears in the preoptic area and contributes mostly astrocytes to the hypothalamus. Shh-expressing progenitors do not contribute to the anterior region at any stage. Finally, we show a gradual shift from neurogenesis to gliogenesis, so that progenitors expressing Shh after E12.5 generate almost exclusively hypothalamic astrocytes.ConclusionsWe define a fate map of the hypothalamus, based on the dynamic expression of Shh in the hypothalamic progenitor zones. We provide evidence that the large neurogenic Shh-expressing progenitor domains of the ventral diencephalon are continuous with those of the midbrain. We demonstrate that the four classical transverse zones of the hypothalamus have clearly defined progenitor domains and that there is little or no cell mixing between the tuberal and anterior or the preoptic and anterior hypothalamus. Finally, we show that, in the tuberal hypothalamus, neurons destined for every mediolateral level are produced during a period of days, in conflict with the current 'three-wave' model of hypothalamic neurogenesis. Our work sets the stage for a deeper developmental analysis of this complex and important brain region.

Highlights

The hypothalamus is a brain region with essential functions for homeostasis and energy metabolism, and alterations of its development can contribute to pathological conditions in the adult, like hypertension, diabetes or obesity
Sonic hedgehog expression in the ventral diencephalon is dynamic It has previously been shown that Shh expression is dynamic in the hypothalamus [10,18], and that these spatial-temporal expression changes are of great functional importance [8,9]
We found that at E8.5, Shh expression was restricted to a narrow medial domain overlying the prechordal plate extending through the presumptive mammillary and tuberal hypothalamus (Figure 1B-F)

Summary

Introduction

The hypothalamus is a brain region with essential functions for homeostasis and energy metabolism, and alterations of its development can contribute to pathological conditions in the adult, like hypertension, diabetes or obesity. Sonic hedgehog (Shh) is a key developmental regulator gene expressed in a dynamic pattern in hypothalamic progenitor cells. The hypothalamus develops from the rostral diencephalon after induction by the underlying prechordal plate. The secreted morphogen Sonic hedgehog (Shh), initially expressed in the prechordal plate, is essential for this inductive process. Shh, which is expressed in a dynamic pattern in the developing ventral hypothalamus, plays a role in these patterning events as well [8,9]. A recent study in which Shh was inactivated in the neuroepithelium, but not in the prechordal plate, demonstrated that neural Shh plays a role in ventrodorsal and rostrocaudal patterning and in establishing lateral hypothalamic neurons but does not seem to be required for regional hypothalamic specification and eyefield separation, for which non-neural Shh signaling from the prechordal plate appears to be sufficient [10]

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