RP58/ZNF238 directly modulates proneurogenic gene levels and is required for neuronal differentiation and brain expansion.

Although neurogenic pathways have been described in the developing neocortex, less is known about mechanisms ensuring correct neuronal differentiation thus also preventing tumor growth. We have shown that RP58 (aka zfp238 or znf238) is highly expressed in differentiating neurons, that its expression is lost or diminished in brain tumors, and that its reintroduction blocks their proliferation. Mice with loss of RP58 die at birth with neocortical defects.

Differential modulation of Sonic-hedgehog-induced cerebellar granule cell precursor proliferation by the IGF signaling network.

The molecular mechanisms regulating organ growth and size remain unclear. Sonic hedgehog (SHH) signaling is a major player in the regulation of cerebellar development: SHH is secreted by Purkinje neurons and acts on the proliferation of granule cell precursors (GCPs) in the external germinal layer. These then become postmitotic and form the internal granular layer but do so in the presence of SHH ligand, begging the question of how the proliferative response to SHH signaling is downregulated in differentiating GCPs.

ZNF238 is expressed in postmitotic brain cells and inhibits brain tumor growth.

Brain tumors such as medulloblastoma (MB) and glioblastoma multiforme (GBM) can derive from neural precursors. For instance, many MBs are thought to arise from the uncontrolled proliferation of cerebellar granule neuron precursors (GNP). GNPs normally proliferate in early postnatal stages in mice but then they become postmitotic and differentiate into granule neurons.

Design and synthesis of inhibitors of Hedgehog signaling based on the alkaloid cyclopamine.

The synthesis and biological evaluation of structurally simplified, metabolically stable cyclopamine-like Sonic Hedgehog (SHH) signaling inhibitors, i.e., 5, is described in four chemical steps from commercially available steroidal precursors.

Pharmacologically active microcarriers releasing glial cell line - derived neurotrophic factor: Survival and differentiation of embryonic dopaminergic neurons after grafting in hemiparkinsonian rats.

To improve the outcome of foetal dopaminergic cell transplantation for the treatment of Parkinson's disease, pharmacologically active microcarriers (PAM) were developed. PAM are able to convey cells on their surface and release a growth factor to improve cell survival, differentiation and integration after brain implantation. Lysozyme-releasing PAM were first produced and characterized.