Neural circuits are assembled with remarkable precision during embryonic development, and the selectivity inherent in their formation helps to define the behavioural repertoire of the mature organism. In the vertebrate central nervous system, this developmental program begins with the differentiation of distinct classes of neurons from progenitor cells located at defined positions within the neural tube. The mechanisms that specify the identity of neural cells have been examined in many regions of the nervous system and reveal a high degree of conservation in the specification of cell fate by key signalling molecules.

/pdf/neuronal-specification-in-the-spinal-cord-inductive-signals-24bsm9hhvx.pdf

Neuronal specification in the spinal cord: inductive signals and transcriptional codes

EVOLUTION: Of Mice . . .

https://arep.med.harvard.edu/pdf/Wichterle02.pdf

Directed Differentiation of Embryonic Stem Cells into Motor Neurons

A major yet unresolved quest in decoding the human genome is the identification of the regulatory sequences that control the spatial and temporal expression of genes. Distant-acting transcriptional enhancers are particularly challenging to uncover because they are scattered among the vast non-coding portion of the genome. Evolutionary sequence constraint can facilitate the discovery of enhancers, but fails to predict when and where they are active in vivo. Here we present the results of chromatin immunoprecipitation with the enhancer-associated protein p300 followed by massively parallel sequencing, and map several thousand in vivo binding sites of p300 in mouse embryonic forebrain, midbrain and limb tissue. We tested 86 of these sequences in a transgenic mouse assay, which in nearly all cases demonstrated reproducible enhancer activity in the tissues that were predicted by p300 binding. Our results indicate that in vivo mapping of p300 binding is a highly accurate means for identifying enhancers and their associated activities, and suggest that such data sets will be useful to study the role of tissue-specific enhancers in human biology and disease on a genome-wide scale.

/pdf/chip-seq-accurately-predicts-tissue-specific-activity-of-1gmd2ayzqt.pdf

ChIP-seq accurately predicts tissue-specific activity of enhancers

Experience exerts a profound influence on the brain and, therefore, on behavior. When the effect of experience on the brain is particularly strong during a limited period in development, this period is referred to as a sensitive period. Such periods allow experience to instruct neural circuits to process or represent information in a way that is adaptive for the individual. When experience provides information that is essential for normal development and alters performance permanently, such sensitive periods are referred to as critical periods. Although sensitive periods are reflected in behavior, they are actually a property of neural circuits. Mechanisms of plasticity at the circuit level are discussed that have been shown to operate during sensitive periods. A hypothesis is proposed that experience during a sensitive period modifies the architecture of a circuit in fundamental ways, causing certain patterns of connectivity to become highly stable and, therefore, energetically preferred. Plasticity that occurs beyond the end of a sensitive period, which is substantial in many circuits, alters connectivity patterns within the architectural constraints established during the sensitive period. Preferences in a circuit that result from experience during sensitive periods are illustrated graphically as changes in a ''stability landscape,'' a metaphor that represents the relative contributions of genetic and experiential influences in shaping the information processing capabilities of a neural circuit. By understanding sensitive periods at the circuit level, as well as understanding the relationship between circuit properties and behavior, we gain a deeper insight into the critical role that experience plays in shaping the development of the brain and behavior.

https://faculty.washington.edu/losterho/knudson_critical_periods_jcn_2004.pdf

Sensitive Periods in the Development of the Brain and Behavior

Eph receptor Tyr kinases and their membrane-tethered ligands, the ephrins, elicit short-distance cell-cell signalling and thus regulate many developmental processes at the interface between pattern formation and morphogenesis, including cell sorting and positioning, and the formation of segmented structures and ordered neural maps. Their roles extend into adulthood, when ephrin-Eph signalling regulates neuronal plasticity, homeostatic events and disease processes. Recently, new insights have been gained into the mechanisms of ephrin-Eph signalling in different cell types, and into the physiological importance of ephrin-Eph in different organs and in disease, raising questions for future research directions.

Mechanisms of ephrin-Eph signalling in development, physiology and disease

Coordinate Roles for LIM Homeobox Genes in Directing the Dorsoventral Trajectory of Motor Axons in the Vertebrate Limb

https://www.cell.com/neuron/pdf/S0896-6273(03)00292-7.pdf

Topographic motor projections in the limb imposed by LIM homeodomain protein regulation of ephrin-A:EphA interactions

https://www.cell.com/neuron/pdf/S0896-6273(05)01049-4.pdf

Distinct Roles for Secreted Semaphorin Signaling in Spinal Motor Axon Guidance

Lim1 encodes a LIM-class homeodomain transcription factor that is essential for head and kidney development. In the developing urogenital system, Lim1 expression has been documented in the Wolffian (mesonephric) duct, the mesonephros, metanephros and fetal gonads. Using, a Lim1 lacZ knock-in allele in mice, we identified a previously unreported urogenital tissue for Lim1 expression, the epithelium of the developing Mullerian duct that gives rise to the oviduct, uterus and upper region of the vagina of the female reproductive tract. Lim1 expression in the Mullerian duct is dynamic, corresponding to its formation and differentiation in females and regression in males. Although female Lim1-null neonates had ovaries they lacked a uterus and oviducts. A novel female mouse chimera assay was developed and revealed that Lim1 is required cell autonomously for Mullerian duct epithelium formation. These studies demonstrate an essential role for Lim1 in female reproductive tract development.

/pdf/requirement-of-lim1-for-female-reproductive-tract-33paqxwtt5.pdf

Artur Kania

Papers

Mechanisms of ephrin-Eph signalling in development, physiology and disease

Coordinate Roles for LIM Homeobox Genes in Directing the Dorsoventral Trajectory of Motor Axons in the Vertebrate Limb

Topographic motor projections in the limb imposed by LIM homeodomain protein regulation of ephrin-A:EphA interactions

Distinct Roles for Secreted Semaphorin Signaling in Spinal Motor Axon Guidance

Requirement of Lim1 for female reproductive tract development