Dendritic Inhibition by Shh Signaling-Dependent Stellate Cell Pool Is Critical for Motor Learning.

Cerebellar inhibitory interneurons are important regulators of neural circuit activity for diverse motor and nonmotor functions. The molecular layer interneurons (MLIs), consisting of basket cells (BCs) and stellate cells (SCs), provide dendritic and somatic inhibitory synapses onto Purkinje cells, respectively. They are sequentially generated in an inside-out pattern from Pax2 immature interneurons, which migrate from the prospective white matter to the ML of the cortex.

Insight into the Etiology of Undifferentiated Soft Tissue Sarcomas from a Novel Mouse Model.

Aberrant activation of the Hedgehog signaling pathway has been linked to the formation of numerous cancer types, including the myogenic soft tissue sarcoma, embryonal rhabdomyosarcoma (eRMS). Here, we report , a novel mouse model in which human GLI2A, a constitutive activator of Hedgehog signaling, induced undifferentiated sarcomas that were phenotypically divergent from eRMS. Rather, sarcomas arising in mice featured some characteristics that were reminiscent of Ewing sarcoma.

Bergmann glial Sonic hedgehog signaling activity is required for proper cerebellar cortical expansion and architecture.

Neuronal-glial relationships play a critical role in the maintenance of central nervous system architecture and neuronal specification. A deeper understanding of these relationships can elucidate cellular cross-talk capable of sustaining proper development of neural tissues. In the cerebellum, cerebellar granule neuron precursors (CGNPs) proliferate in response to Purkinje neuron-derived Sonic hedgehog (Shh) before ultimately exiting the cell cycle and migrating radially along Bergmann glial fibers.

Lkb1 regulates granule cell migration and cortical folding of the cerebellar cortex.

Cerebellar growth and foliation require the Hedgehog-driven proliferation of granule cell precursors (GCPs) in the external granule layer (EGL). However, that increased or extended GCP proliferation generally does not elicit ectopic folds suggests that additional determinants control cortical expansion and foliation during cerebellar development. Here, we find that genetic loss of the serine-threonine kinase Liver Kinase B1 (Lkb1) in GCPs increased cerebellar cortical size and foliation independent of changes in proliferation or Hedgehog signaling.

BET bromodomain inhibitors suppress EWS-FLI1-dependent transcription and the IGF1 autocrine mechanism in Ewing sarcoma.

Ewing sarcoma is driven by characteristic chromosomal translocations between the EWSR1 gene with genes encoding ETS family transcription factors (EWS-ETS), most commonly FLI1. However, direct pharmacological inhibition of transcription factors like EWS-FLI1 remains largely unsuccessful. Active gene transcription requires orchestrated actions of many epigenetic regulators, such as the bromodomain and extra-terminal domain (BET) family proteins.

An in vivo chemical genetic screen identifies phosphodiesterase 4 as a pharmacological target for hedgehog signaling inhibition.

Hedgehog (Hh) signaling plays an integral role in vertebrate development, and its dysregulation has been accepted widely as a driver of numerous malignancies. While a variety of small molecules target Smoothened (Smo) as a strategy for Hh inhibition, Smo gain-of-function mutations have limited their clinical implementation. Modulation of targets downstream of Smo could define a paradigm for treatment of Hh-dependent cancers.

The Purkinje neuron acts as a central regulator of spatially and functionally distinct cerebellar precursors.

The prospective white matter (PWM) in the nascent cerebellum contains a transient germinal compartment that produces all postnatally born GABAergic inhibitory interneurons and astrocytes. However, little is known about the molecular identity and developmental potential of resident progenitors or key regulatory niche signals. Here, we show that neural stem-cell-like primary progenitors (Tnc(YFP-low) CD133(+)) generate intermediate astrocyte (Tnc(YFP-low) CD15(+)) precursors and GABAergic transient amplifying (Ptf1a(+)) cells.

Expression and localization of myosin-1d in the developing nervous system.

Myosin-1d is a monomeric actin-based motor found in a wide range of tissues, but highly expressed in the nervous system. Previous microarray studies suggest that myosin-1d is found in oligodendrocytes where transcripts are upregulated during the maturation of these cells. Myosin-1d was also identified as a component of myelin-containing subcellular fractions in proteomic studies and mutations in MYO1D have been linked to autism.

Transventricular delivery of Sonic hedgehog is essential to cerebellar ventricular zone development.

Cerebellar neurons are generated from two germinal neuroepithelia: the ventricular zone (VZ) and rhombic lip. Signaling mechanisms that maintain the proliferative capacity of VZ resident progenitors remain elusive. We reveal that Sonic hedgehog (Shh) signaling is active in the cerebellar VZ and essential to radial glial cell proliferation and expansion of GABAergic interneurons.

Sonic hedgehog signaling regulates a novel epithelial progenitor domain of the hindbrain choroid plexus.

Choroid plexuses (ChPs) are vascularized secretory organs involved in the regulation of brain homeostasis, and function as the blood-cerebrospinal fluid (CSF) barrier. Despite their crucial roles, there is limited understanding of the regulatory mechanism driving ChP development. Sonic hedgehog (Shh), a secreted signal crucial for embryonic development and cancer, is strongly expressed in the differentiated hindbrain ChP epithelium (hChPe).