Aberrant FGF signaling promotes granule neuron precursor expansion in SHH subgroup infantile medulloblastoma.

Mutations in Sonic Hedgehog (SHH) signaling pathway genes, for example, (SUFU), drive granule neuron precursors (GNP) to form medulloblastomas (MB). However, how different molecular lesions in the Shh pathway drive transformation is frequently unclear, and mutations in the cerebellum seem distinct. In this study, we show that fibroblast growth factor 5 (FGF5) signaling is integral for many infantile MB cases and that expression is uniquely upregulated in infantile MB tumors.

The Neocortical Progenitor Specification Program Is Established through Combined Modulation of SHH and FGF Signaling.

Neuronal progenitors in the developing forebrain undergo dynamic competence states to ensure timely generation of specific excitatory and inhibitory neuronal subtypes from distinct neurogenic niches of the dorsal and ventral forebrain, respectively. Here we show evidence of progenitor plasticity when Sonic hedgehog (SHH) signaling is left unmodulated in the embryonic neocortex of the mammalian dorsal forebrain. We found that, at early stages of corticogenesis, loss of Suppressor of Fused (Sufu), a potent inhibitor of SHH signaling, in neocortical progenitors, altered the transcriptomic landscape of male mouse embryos.

Suppressor of Fused regulates the proliferation of postnatal neural stem and precursor cells via a Gli3-dependent mechanism.

The ventricular-subventricular zone (V-SVZ) of the forebrain is the source of neurogenic stem/precursor cells for adaptive and homeostatic needs throughout the life of most mammals. Here, we report that Suppressor of Fused (Sufu) plays a critical role in the establishment of the V-SVZ at early neonatal stages by controlling the proliferation of distinct subpopulations of stem/precursor cells. Conditional deletion of Sufu in radial glial progenitor cells (RGCs) at E13.

Sonic Hedgehog Signaling Rises to the Surface: Emerging Roles in Neocortical Development.

The mammalian neocortex is composed of a diverse population of neuronal and glial cells that are crucial for cognition and consciousness. Orchestration of molecular events that lead to the production of distinct cell lineages is now a major research focus. Recent studies in mammalian animal models reveal that Sonic Hedgehog (Shh) signaling plays crucial roles in this process.

The Dorsal Wave of Neocortical Oligodendrogenesis Begins Embryonically and Requires Multiple Sources of Sonic Hedgehog.

Neural progenitor cells in the developing dorsal forebrain give rise to excitatory neurons, astrocytes, and oligodendrocytes for the neocortex. While we are starting to gain a better understanding about the mechanisms that direct the formation of neocortical neurons and astrocytes, far less is known about the molecular mechanisms that instruct dorsal forebrain progenitors to make oligodendrocytes. In this study, we show that Sonic hedgehog (Shh) signaling is required in dorsal progenitors for their late embryonic transition to oligodendrogenesis.

The Crossroads of Neural Stem Cell Development and Tumorigenesis.

Isolated brain tumors contain cells that exhibit stem cell features and a tissue microenvironment bearing remarkable similarities to the normal neurogenic niche. This supports the idea that neural stem (NSCs) or progenitor cells, and their progeny are the likely tumor cell(s) of origin. This prompted the investigation of the relationship between NSCs/progenitors and the initiation of tumorigenesis.

Loss of Suppressor of Fused in Mid-Corticogenesis Leads to the Expansion of Intermediate Progenitors.

Neural progenitors in the embryonic neocortex must be tightly regulated in order to generate the correct number and projection neuron subtypes necessary for the formation of functional neocortical circuits. In this study, we show that the intracellular protein Suppressor of Fused (Sufu) regulates the proliferation of intermediate progenitor (IP) cells at later stages of corticogenesis to affect the number of Cux1+ upper layer neurons in the postnatal neocortex. This correlates with abnormal levels of the repressor form of Gli3 (Gli3R) and the ectopic expression of Patched 1 (Ptch1), a Sonic Hedgehog (Shh) target gene.

Suppressor of Fused Is Critical for Maintenance of Neuronal Progenitor Identity during Corticogenesis.

Proper lineage progression and diversification of neural progenitor cells (NPCs) ensures the generation of projection neuron (PN) subtypes in the mammalian neocortex. Here, we show that Suppressor of Fused (Sufu) controls PN specification by maintaining the identity of NPCs in the embryonic neocortex. Deletion of Sufu in NPCs of the E10.