Johnson Lab

Research

The research in the Johnson Lab is focused on vertebrate nervous system development during the transition from proliferating neural stem cells to differentiating neurons and glia. We use the bHLH family of transcription factors to probe the molecular mechanisms controlling the balance of neural progenitor cell maintenance and differentiation, and the generation of neuronal diversity. Alteration in function and expression of the neural bHLH factors result in disturbances of connectivity, imbalances in excitatory and inhibitory neuron formation, and loss of control of neural cell number. Our focus on understanding how transcription factors regulate neuronal differentiation and diversity has direct implications for stem cell biology and cancer.

In the dorsal spinal cord, critical for processing somatosensory information, we have defined a shared function for the neural bHLH transcription factors in neuronal differentiation and distinct functions in neuronal subtype specification. One major impact of this research effort has been in identifying and characterizing enhancer sequences for these genes that direct spatially and temporally discrete transcription during neural development. These sequences and subsequent transgenic mouse models have been used widely in the research community for studies in the development of the spinal cord and brain, inner ear, retina, olfactory epithelium, adult neurogenesis, stem cell biology, and cancer. We also have made significant contributions to understanding the function of these factors in regulating the transition of progenitor cells to differentiating neurons, and oligodendrocytes. These studies use mouse models and overexpression in chick neural tubes to probe gene function, mechanisms of action of the bHLH factors, and the identity and fates of progenitors expressing each factor. These efforts have revealed fundamental molecular mechanisms and rationales for how a nervous system is generated. More recently, we are taking advantage of major advances in technology that allow for a deeper understanding of how transcription factors function in vivo by identifying direct transcriptional targets genome-wide using ChIP-seq and RNA-seq strategies.

Currently, there are three main areas of research in my laboratory. 1) regulation and function of ASCL1 in embryonic neural development and cancer such as neuroendocrine lung cancer, 2) epigenetic and transcriptional control balancing the generation of inhibitory and excitatory neurons in the dorsal spinal cord, and 3) uncovering functions of the direct downstream targets of neural bHLH factors in neural differentiation, neuronal sub-type specification, and cancer. The neural bHLH transcription factors sit at critical choice points for generating the correct number of neurons of specific types required for proper neuronal circuit function. Our focus on understanding how transcription factors regulate neuronal differentiation and diversity has direct implications for stem cell biology and cancer. A case in point is ASCL1; important in reprogramming non-neuronal cells to neurons, and a requirement for tumor growth in small cell lung carcinoma.

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