Sonic Hedgehog: a morphogen involved in axon guidance

A morphogen is classically defined as a signaling molecule that elicits different cellular responses depending on its concentration. More specifically, morphogens are secreted molecules that drive the organization of regional groups of cells into patterns. The absolute concentration of the morphogen acting on any one cell determines developmental fate.1, 2 An axon guidance molecule, by contrast, has only one function - to either attract or repel a motile growth cone. In contrast to morphogens, their guidance function is determined by a cell's ability to detect a change in guidance molecule concentration over distance. Until recently, morphogens and guidance molecules were considered structurally and functionally distinct. Now, however, it would appear that select, early-expressed morphogens can be temporally "recycled" and serve as axon guidance cues. Sonic hedgehog (Shh), along with members of the Wnt and bone morphogenetic protein (BMP) families, is a molecule that acts early as a morphogen to determine neuronal fate and later as an axon guidance factor to help direct the paths of developing neurons (Figure 1).3, 4, 5, 6

A gradient of Shh acts in the early neural tube to specify ventral neurons (V0-V3 and MN), while a BMP gradient specifies dorsal neurons.
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Figure 1. A gradient of Shh acts in the early neural tube to specify ventral neurons (V0-V3 and MN), while a BMP gradient specifies dorsal neurons. Vertebrate commissural neurons of the dorsolateral spinal cord take a ventral trajectory toward the floor plate, cross the midline, and then turn, following along the floor plate, while moving anteriorly towards the brain. Shh, BMP, and Wnt are morphogens that help guide commissural axons along this path

As a morphogen, Shh participates in the patterning of the developing spinal cord. Following closure of the neural tube, commissural (crossing; contralateral) and association (same side; ipsilateral) neurons develop in the dorsal half of the cord, while inter- and motor-neurons form in the ventral half of the cord. Shh is secreted by the ventral floor plate. As the concentration of Shh diminishes dorsally, at least five distinct neuron cell types form along its gradient, demonstrating morphogenic ability. Four interneuron cell types (termed V0-V3) plus lower motor neurons (MN) are induced through Shh-mediated activation and repression of homeodomain transcription factors. Based on the level of Shh concentration, different thresholds for repression and activation of the transcription factors give rise to a "code" of progenitor domains.7 Thus, neurons generated in the more ventral progenitor domains, nearest the floor plate, result from higher levels of Shh.7, 8

As an axon guidance molecule, Shh impacts the positioning of dorsal commissural axons following its morphogenic effects on neuron formation. Initially, BMP-7, produced dorsally, prohibits developing dorsal axons from crossing the midline in the region of the roof plate.7, 9 This leaves only a ventral direction for growth. Once they have arrived at their ventral location, both Shh and Netrin-1 collaborate to chemoattract dorsal axons towards the midline.10 Remarkably, following crossing of the midline, Shh acts as a chemorepellent rather than chemoattractant. Shh, together with an anterior-to-posterior Wnt gradient plus an Ephrin B signaling cascade, directs neurons to turn at a 90° angle and continue migration in the anterior direction towards the brain.11, 12, 13, 14

Distinct receptors on axons help mediate the differential responses to Shh. It is suggested that BOC (Brother of CDO), working in concert with Smoothened, mediates chemoattraction, while a temporally-regulated Hip (Hedgehog Interacting Protein) receptor mediates chemorepulsion.4, 13, 15 Moreover, morphogenic functions of Shh to determine neuronal cell fate are thought to signal through the Patched (ligand binding) and Smoothened (signal transducing) receptors.7


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