Disrupted Hypothalamo-Pituitary Axis in Association With Reduced SHH Underlies the Pathogenesis of NOTCH-Deficiency.

Context: In human, Sonic hedgehog (SHH) haploinsufficiency is the predominant cause of holoprosencephaly, a structural malformation of the forebrain midline characterized by phenotypic heterogeneity and incomplete penetrance. The NOTCH signaling pathway has recently been associated with holoprosencephaly in humans, but the precise mechanism involving NOTCH signaling during early brain development remains unknown.

Objective: The aim of this study was to evaluate the relationship between SHH and NOTCH signaling to determine the mechanism by which NOTCH dysfunction could cause midline malformations of the forebrain.

Abnormal Photic Entrainment to Phase-Delaying Stimuli in the R6/2 Mouse Model of Huntington's Disease, despite Retinal Responsiveness to Light.

The circadian clock located in the suprachiasmatic nucleus (SCN) in mammals entrains to ambient light via the retinal photoreceptors. This allows behavioral rhythms to change in synchrony with seasonal and daily changes in light period. Circadian rhythmicity is progressively disrupted in Huntington's disease (HD) and in HD mouse models such as the transgenic R6/2 line.

Regulation of downstream neuronal genes by proneural transcription factors during initial neurogenesis in the vertebrate brain.

Background: Neurons arise in very specific regions of the neural tube, controlled by components of the Notch signalling pathway, proneural genes, and other bHLH transcription factors. How these specific neuronal areas in the brain are generated during development is just beginning to be elucidated. Notably, the critical role of proneural genes during differentiation of the neuronal populations that give rise to the early axon scaffold in the developing brain is not understood.

Evolutionary Conservation of the Early Axon Scaffold in the Vertebrate Brain.

The early axon scaffold is the first axonal structure to appear in the rostral brain of vertebrates, paving the way for later, more complex connections. Several early axon scaffold components are conserved between all vertebrates; most notably two main ventral longitudinal tracts, the tract of the postoptic commissure and the medial longitudinal fascicle. While the overall structure is remarkably similar, differences both in the organization and the development of the early tracts are apparent.

Dynamic expression of Notch-dependent neurogenic markers in the chick embryonic nervous system.

The establishment of a functional nervous system requires a highly orchestrated process of neural proliferation and differentiation. The evolutionary conserved Notch signaling pathway is a key regulator of this process, regulating basic helix-loop-helix (bHLH) transcriptional repressors and proneural genes. However, little is known about downstream Notch targets and subsequently genes required for neuronal specification.

Notch signaling and proneural genes work together to control the neural building blocks for the initial scaffold in the hypothalamus.

The vertebrate embryonic prosencephalon gives rise to the hypothalamus, which plays essential roles in sensory information processing as well as control of physiological homeostasis and behavior. While patterning of the hypothalamus has received much attention, initial neurogenesis in the developing hypothalamus has mostly been neglected. The first differentiating progenitor cells of the hypothalamus will give rise to neurons that form the nucleus of the tract of the postoptic commissure (nTPOC) and the nucleus of the mammillotegmental tract (nMTT).

The tumor suppressor Nf2 regulates corpus callosum development by inhibiting the transcriptional coactivator Yap.

The corpus callosum connects cerebral hemispheres and is the largest axon tract in the mammalian brain. Callosal malformations are among the most common congenital brain anomalies and are associated with a wide range of neuropsychological deficits. Crossing of the midline by callosal axons relies on a proper midline environment that harbors guidepost cells emitting guidance cues to instruct callosal axon navigation.

Development of the Early Axon Scaffold in the Rostral Brain of the Small Spotted Cat Shark (Scyliorhinus canicula) Embryo.

The cat shark is increasingly used as a model for Chondrichthyes, an evolutionarily important sister group of the bony vertebrates that include teleosts and tetrapods. In the bony vertebrates, the first axon tracts form a highly conserved early axon scaffold. The corresponding structure has not been well characterised in cat shark and will prove a useful model for comparative studies.

Novel genes upregulated when NOTCH signalling is disrupted during hypothalamic development.

Background: The generation of diverse neuronal types and subtypes from multipotent progenitors during development is crucial for assembling functional neural circuits in the adult central nervous system. It is well known that the Notch signalling pathway through the inhibition of proneural genes is a key regulator of neurogenesis in the vertebrate central nervous system. However, the role of Notch during hypothalamus formation along with its downstream effectors remains poorly defined.

Development of the early axon scaffold in the rostral brain of the chick embryo.

The arrangement of the early nerve connections in the embryonic vertebrate brain follows a well-conserved pattern, forming the early axon scaffold. The early axon tracts have been described in a number of anamniote species and in mouse, but a detailed analysis in chick is lacking. We have used immunostaining, axon tracing and in situ hybridisation to analyse the development of the early axon scaffold in the embryonic chick brain in relation to the neuromeric organisation of the brain.