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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.

Activating protein 2␣ (AP-2␣) is known to be expressed in the retina, and AP-2␣-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-2␣ and created a conditional deletion of AP-2␣ in the developing retina. AP-2␣ exhibited a distinct expression pattern in the developing inner nuclear layer of the retina, and colocalization studies indicated that AP-2␣ was exclusively expressed in postmitotic amacrine cell populations. Targeted deletion of AP-2␣ in the developing retina did not result in observable retinal defects. Further examination of AP-2␣-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-2␣ 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.The retina is an extension of the central nervous system derived from the forebrain neural ectoderm. During vertebrate eye development, the diencephalon evaginates to form optic vesicles, which subsequently invaginate to form a bilayered optic cup. The inner layer of the optic cup will give rise to the neural retina (NR), and the outer layer becomes the retinal pigmented epithelium (RPE) (13). Six principal types of neurons and the Müller glia cells that comprise the NR are generated in a fixed, overlapping chronological order (69). Ganglion cells are "born" (i.e., become postmitotic) first, followed by amacrine, horizontal, and cone photoreceptor cells, and ending with bipolar and Müller glia cells. The birth of rod photoreceptors spans nearly the entire period of retinal histogenesis, which begins at embryonic day 10.5 (E10.5) in mice and continues for approximately 3 weeks, ending at postnatal day 11 (P11) (69). A "central-to-peripheral" gradient of differentiation has been described in the NR, where the genesis of a particular cell type begins in the central retina (near the optic nerve head) and spreads toward the peripheral retina (next to the ciliary body) (26,37,47).A range of extrinsic and intrinsic factors control the many steps that retinal progenitor cells (RPCs) progress through during development, including cell cycle exit, cell fate bias or commitment, and differentiation into a functional neuron or glial cell. The prevailing model to explain how different retinal cell fates are determined from multipotent progenitors suggests that RPCs progress through states of competence, in which their continually changing intrinsic properties determine how they will respond to external signals at given times duri...

Background 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. Results 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. Conclusions 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.

Appropriate development of the retina and optic nerve requires that the forebrain-derived optic neuroepithelium undergoes a precisely coordinated sequence of patterning and morphogenetic events, processes which are highly influenced by signals from adjacent tissues. Our previous work has suggested that transcription factor activating protein-2 alpha (AP-2alpha; Tcfap2a) has a non-cell autonomous role in optic cup (OC) development; however, it remained unclear how OC abnormalities in AP-2alpha knockout (KO) mice arise at the morphological and molecular level. In this study, we show that patterning and morphogenetic defects in the AP-2alpha KO optic neuroepithelium begin at the optic vesicle stage. During subsequent OC formation, ectopic neural retina and optic stalk-like tissue replaced regions of retinal pigment epithelium. AP-2alpha KO eyes also displayed coloboma in the ventral retina, and a rare phenotype in which the optic stalk completely failed to extend, causing the OCs to be drawn inward to the midline. We detected evidence of increased sonic hedgehog signaling in the AP-2alpha KO forebrain neuroepithelium, which likely contributed to multiple aspects of the ocular phenotype, including expansion of PAX2-positive optic stalk-like tissue into the OC. Our data suggest that loss of AP-2alpha in multiple tissues in the craniofacial region leads to severe OC and optic stalk abnormalities by disturbing the tissue-tissue interactions required for ocular development. In view of recent data showing that mutations in human TFAP2A result in similar eye defects, the current findings demonstrate that AP-2alpha KO mice provide a valuable model for human ocular disease.