Sonic hedgehog signaling in the postnatal brain

Abstract

Sonic hedgehog (Shh) is a pleiotropic factor in the developing central nervous system (CNS), driving proliferation, specification, and axonal targeting in multiple sites within the forebrain, hindbrain, and spinal cord. Studies in embryonic CNS have shown how gradients of this morphogen are translated by neuroepithelial precursors to determine the types of neurons and glial cells they produce [1,2]. Shh also has a well-characterized role as a mitogen for specific progenitor cell types in neural development [3,4]. As we begin to appreciate that Shh continues to act in the adult brain, a central question is what functional role this ligand plays when major morphogenetic and proliferative processes are no longer in operation. A second fundamental question is whether similar signaling mechanisms operate in embryonic and adult CNS. In the two major germinal zones of the adult brain, Shh signaling modulates the self-renewal and specification of astrocyte-like primary progenitors, frequently referred to as neural stem cells (NSCs). It also may regulate the response of the mature brain to injury, as Shh signaling has been variously proposed to enhance or inhibit the development of a reactive astrocyte phenotype. The identity of cells producing the Shh ligand, and the conditions that trigger its release, are also areas of growing interest; both germinal zones in the adult brain contain Shh-responsive cells but do not autonomously produce this ligand. Here, we review recent findings revealing the function of this fascinating pathway in the postnatal and adult brain, and highlight ongoing areas of investigation into its actions long past the time when it shapes the developing brain.

Keywords: Astrocytes; Brain tumor stem cells; Neural stem cells; Primary cilium; Reactive astrocytes; Sonic hedgehog; Stem cell microdomains; Subgranular zone; Ventricular-subventricular zone.

Figure 1

Expression of Shh Pathway Components in the Mature Brain. Coronal sections of adult brain are shown from anterior (left) to posterior (right). The ventricles, which contain cerebrospinal fluid, are shown in black. Specific anatomical regions discussed in the text are indicated in the top row of sections, including the olfactory bulb (OB), ventricular-subventricular zone (V-SVZ), and subgranular zone (SGZ) in the dentate gyrus. Locations where Shh, Smo, and Gli1 (downstream transcriptional activator) expression have been reported are indicated by colored dots. Both the V-SVZ and SGZ contain Smo-expressing astrocyte-like stem cells, some fraction of which also express Gli1. The cortex (in the dorsal portion of each slice) and parts of the ventral forebrain also contain Smo / Gli1-expressing astrocytes. By contrast, Shh-producing cells are often located in distinct subregions from Shh-responsive cells, with Shh-producing neurons found in the septum (Sep), multiple areas in the ventral forebrain, and the substantia nigra (SN).

Figure 2

Forced Activation of Shh Signaling Respecifies Neuronal Progeny. Localized dorsal injection of Ad:GFAPpCre virus (shown in green), which drives recombination in GFAP-expressing stem cells and astrocytes, was used to induce expression of a GFP reporter in combination with a conditional SmoM2 allele. Dorsal stem cells expressing only GFP primarily generate superficial granule cells (shown in blue). In contrast, expression of GFP and SmoM2 re-specifies these dorsal neural stem cells and results in most of these progenitors producing deep granule cells (shown in red), mimicking the behavior of ventral neural stem cells. This forced activation of Hh signaling in dorsal neural stem cells also results in the up-regulation of gli1 transcript in labeled neural stem cells (not shown).