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How do you build a brain?

Our brains allow us to process and perceive the world, and they receive information from our sensory systems.

The visual system is an ideal model to study neural development; although it is incredibly complex, it consists of repeating units that allow for simplification of study. Among different models, the fruit fly Drosophila melanogaster possesses a wealth of tools that provide us with unparalleled access, allowing us to study the process of development with a level of detail not yet possible in higher organisms.

Previous work

As a postdoctoral fellow in Claude Desplan's lab, Jennifer Malin studied how stem cells produce different classes of neurons in distinct proportions. Focusing on the inhibitory interneurons of the Drosophila optic lobe (i.e. Distal medulla, or Dm neurons), Jennifer explored how the factors that pattern stem cells produce neurons in reproducible numbers. Previous work showed that the neuroepithelial progenitors that produce Dm neurons are spatially divided into distinct subdomains based on the expression of different transcription factors. These factors act with temporally restricted genes expressed in neural stem cells to produce neurons of different fates. However, it was unknown the fates of the neurons born from each domain, nor was it known how these stem cells produced neurons in reproducible proportions.

With colleagues from the Desplan lab, Jennifer mapped the spatial origins of each neuron in the Drosophila visual system. She found that the size of the domain of origin correlates with the total number of Dm neurons generated from each class. That is, rare cell types are born from small subdomains, while abundant cell types are born from larger ones. However, spatial patterning from transcription factors alone was not sufficient to account for differences in cell number between similar types.

Jennifer found that diffusible gradients of factors called morphogens (namely the conserved proteins BMP/Dpp) act in a concentration dependent manner to regulate the cell fates of neighboring cells. These morphogens provide a second layer of patterning that acts in concert with the previously-discovered transcription factors to promote cell fate of the rarest subtypes. Although most previous studies implicate cell division and cell death in promoting fate, Jennifer's work showed that patterning-based mechanisms are also an important regulator of cell number (Malin and Desplan 2024).

Current Research:

Morphogenetic regulation of cell fate/cell type proportions:

The neuroepithelium that produces Drosophila visual system stem cells is subdivided into domains based on the expression of distinct transcription factors and growth factors (see previous research). At the posterior edge of the neuroepithelium, the conserved morphogen Dpp/BMP is secreted from the posterior edge to produce pools of stem cells that specify neurons in distinct proportions.

Although the concentration of Dpp is sufficient to distinguish these similar cell types, it is not known what factors act downstream of Dpp to promote cell fate. Nor is it known how the levels of Dpp itself are titrated to allow for a reproducible cell fate outcome.

One arm of our lab will study the secreted and cell-intrinsic genes required to ensure robust cell type specification from a diffusible signal. We will use the Dm neurons Dm1/4/12 and p/yDm8 as a model.

How do neurons scale their arbors to evenly sample their environment?

To perceive the visual world, neurons must evenly distribute themselves and produce neurites of uniform size. In the Drosophila optic lobe, one class of inhibitory interneurons called Distal medulla neurons regulates the flow of visual information through the integration of signals received from multiple photoreceptor columns.

Most work on neurite scaling in other organisms suggests that neurons scale through contact-mediated self-avoidance. However, when we ablate half of all Dm4 neurons during development, the arbor size does not change, suggesting that these cells may use a different mechanism.

Upon screening through genes specifically expressed in Dm4s, we found a number of candidates disrupt the shape, size, and tiling of Dm4 neurons. Our lab will characterize the roles of these genes in promoting neuron targeting; as many of these genes are conserved, we will identify broadly-used mechanisms that scale neurites, allowing neurons to find the correct targets and to evenly sample their environment.