Sonic hedgehog (Shh)-Gli signaling controls neural progenitor cell division in the developing tectum in zebrafish

Abstract

Despite considerable progress, the mechanisms that control neural progenitor differentiation and behavior, as well as their functional integration into adult neural circuitry, are far from being understood. Given the complexity of the mammalian brain, non-mammalian models provide an excellent model to study neurogenesis, including both the cellular composition of the neurogenic microenvironment, and the factors required for precursor growth and maintenance. In particular, we chose to address the question of the control of progenitor proliferation by Sonic hedgehog (Shh) using the zebrafish dorsal mesencephalon, known as the optic tectum (OT), as a model system. Here we show that either inhibiting pharmacologically or eliminating hedgehog (Hh) signaling by using mutants that lack essential components of the Hh pathway reduces neural progenitor cell proliferation affecting neurogenesis in the OT. On the contrary, pharmacological gain-of-function experiments result in significant increase in proliferation. Importantly, Shh-dependent function controls neural progenitor cell behavior as sox2-positive cell populations were lost in the OT in the absence of Hh signaling, as evidenced in slow-muscle-omitted (smu) mutants and with timed cyclopamine inhibition. Expressions of essential components of the Hh pathway reveal for the first time a late dorsal expression in the embryonic OT. Our observations argue strongly for a role of Shh in neural progenitor biology in the OT and provide comparative data to our current understanding of progenitor/stem cell mechanisms that place Shh as a key niche factor in the dorsal brain.

Activation of Sonic hedgehog signaling in neural progenitor cells promotes glioma development in the zebrafish optic pathway

“…These observations of abnormal brain development conform to studies suggesting that Shh signaling acts as a mitogen to modulate neural progenitor proliferation in both mouse dorsal brain 22 and zebrafish optic tectum. 23 …”

Arsenic inhibits hedgehog signaling during P19 cell differentiation

“…Studies have shown that lack of Shh signaling disrupts dorso-ventral pattering within the neural tube in mice (Chiang et al , 1996; Murdoch and Copp, 2010). In zebrafish, inhibition of Shh signaling by using mutants that lack essential components of the Shh pathway, like Smoothen ( Smo ) and Gli , reduces neural progenitor cell proliferation in the dorsal mesencephalon (Feijoo et al , 2011). Moreover, mice with mutations in Shh and Gli show a delay in motor neuron differentiation in spinal cord, suggesting that Shh signaling is also important in neurogenesis (Oh et al , 2009).…”

Yeast-based assay identifies novel Shh/Gli target genes in vertebrate development

“…At 48 hpf wild-type c-myc expression is found in the posterior margin of the optic tectum, recently identified as an important proliferative zone in the dorsal brain of teleosts (Figure 5A, arrow) [18,19]. The mRNA can also be detected in the eye and liver (Figure 5A asterisk).…”