[Show abstract][Hide abstract] ABSTRACT: Chromatin compaction mediates progenitor to post-mitotic cell transitions and modulates gene expression programs, yet the mechanisms are poorly defined. Snf2h and Snf2l are ATP-dependent chromatin remodelling proteins that assemble, reposition and space nucleosomes, and are robustly expressed in the brain. Here we show that mice conditionally inactivated for Snf2h in neural progenitors have reduced levels of histone H1 and H2A variants that compromise chromatin fluidity and transcriptional programs within the developing cerebellum. Disorganized chromatin limits Purkinje and granule neuron progenitor expansion, resulting in abnormal post-natal foliation, while deregulated transcriptional programs contribute to altered neural maturation, motor dysfunction and death. However, mice survive to young adulthood, in part from Snf2l compensation that restores Engrailed-1 expression. Similarly, Purkinje-specific Snf2h ablation affects chromatin ultrastructure and dendritic arborization, but alters cognitive skills rather than motor control. Our studies reveal that Snf2h controls chromatin organization and histone H1 dynamics for the establishment of gene expression programs underlying cerebellar morphogenesis and neural maturation.
[Show abstract][Hide abstract] ABSTRACT: Norrie Disease (ND) is a congenital disorder characterized by retinal hypovascularization and cognitive delay. ND has been linked to mutations in Norrie Disease Protein (Ndp), which encodes the secreted protein Norrin. Norrin functions as a secreted angiogenic factor, while its role in neural development has not been assessed. Here we show that Ndp expression is initiated in retinal progenitors in response to Hedgehog (Hh) signaling, which induces Gli2 binding to the Ndp promoter. Using a combination of genetic epistasis and acute RNAi-knockdown approaches we show that Ndp is required downstream of Hh activation to induce retinal progenitor proliferation in the retina. Strikingly, Ndp regulates the rate of cell cycle re-entry and not cell cycle kinetics, thereby uncoupling the self-renewal and cell cycle progression functions of Hh. Taken together, we have uncovered a cell autonomous function for Ndp in retinal progenitor proliferation that is independent of its function in the retinal vasculature, which could explain the neural defects associated with ND.
Human Molecular Genetics 11/2012; 22(5). DOI:10.1093/hmg/dds505 · 6.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The vertebrate retina is a well-characterized and tractable model for studying neurogenesis. Retinal neurons and glia are generated in a conserved sequence from a pool of multipotent progenitor cells, and numerous cell fate determinants for the different classes of retinal cell types have been identified. Here, we summarize several recent developments in the field that have advanced understanding of the regulation of multipotentiality and temporal competence of progenitors. We also discuss recent insights into the relative influence of lineage-based versus stochastic modes of cell fate determination. Enhancing and integrating knowledge of the molecular and genetic machinery underlying retinal development is critically important for understanding not only normal developmental mechanisms, but also therapeutic interventions aimed at restoring vision loss.
Trends in Neurosciences 06/2012; 35(9):565-73. DOI:10.1016/j.tins.2012.05.004 · 13.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We have previously shown that the transcription factor AP-2α (Tcfap2a) is expressed in postmitotic developing amacrine cells in the mouse retina. Although retina-specific deletion of Tcfap2a did not affect retinogenesis, two other family members, AP-2β and AP-2γ, showed expression patterns similar to AP-2α.
Here we show that, in addition to their highly overlapping expression patterns in amacrine cells, AP-2α and AP-2β are also co-expressed in developing horizontal cells. AP-2γ expression is restricted to amacrine cells, in a subset that is partially distinct from the AP-2α/β-immunopositive population. To address possible redundant roles for AP-2α and AP-2β during retinogenesis, Tcfap2a/b-deficient retinas were examined. These double mutants showed a striking loss of horizontal cells and an altered staining pattern in amacrine cells that were not detected upon deletion of either family member alone.
These studies have uncovered critical roles for AP-2 activity in retinogenesis, delineating the overlapping expression patterns of Tcfap2a, Tcfap2b, and Tcfap2c in the neural retina, and revealing a redundant requirement for Tcfap2a and Tcfap2b in horizontal and amacrine cell development.
[Show abstract][Hide abstract] ABSTRACT: Activating protein 2α (AP-2α) is known to be expressed in the retina, and AP-2α-null mice exhibit defects in the developing
optic cup, including patterning of the neural retina (NR) and a replacement of the dorsal retinal pigmented epithelium (RPE)
with NR. In this study, we analyzed the temporal and spatial retinal expression patterns of AP-2α and created a conditional
deletion of AP-2α in the developing retina. AP-2α exhibited a distinct expression pattern in the developing inner nuclear
layer of the retina, and colocalization studies indicated that AP-2α was exclusively expressed in postmitotic amacrine cell
populations. Targeted deletion of AP-2α in the developing retina did not result in observable retinal defects. Further examination
of AP-2α-null mutants revealed that the severity of the RPE defect was variable and, although defects in retinal lamination
occur at later embryonic stages, earlier stages showed normal lamination and expression of markers for amacrine and ganglion
cells. Together, these data demonstrate that, whereas AP-2α alone does not play an intrinsic role in retinogenesis, it has
non-cell-autonomous effects on optic cup development. Additional expression analyses showed that multiple AP-2 proteins are
present in the developing retina, which will be important to future studies.