Main projects

• HINDBRAIN DEVELOPMENT:

From neural progenitor/stem cells (NPSCs) to neuronal networks. The hindbrain is a special domain in the cranial neural tube fated to give rise to the brainstem and cerebellum. Pioneer studies in the early 90’s have identified the segmentation of the early hindbrain into repetitive rhombomeres as a fascinating model for studying CNS development. The ordered and conserved way in which the hindbrain develops in all vertebrates, as well as its unique topography and resemblance to evolutionarily precedent embryonic structures, inspire developmental biologists for many decades.  

Hindbrain rhombomeres are separated by well-defined boundaries in all vertebrates. The function of these unique cellular, molecular and morphologically distinctive domains is vague, especially in amniotes. Using chick and mouse embryos as model systems, our lab has discovered that hindbrain boundaries act as repetitive niches of NPSCs that accumulate in-between the actively-differentiating rhombomeres. By integrating multiple developmental, omics and stem-cell based approaches in- vivo and in-vitro, we continue to explore the genetic network that orchestrates the balance between NPSCs, neural differentiation and the assembly of axonal circuits in the developing hindbrain.

Enriched expression of the NPSC marker Sox2 and the ECM marker Chondroitin Sulpahte Proteoglycan (CSPG) at hindbrain boundaries

The unique morphology of the hindbrain in E3 chick embryo as evaluated by scanning electron microscopy and IMARIS analyses

 

R, Rhombomers

Modification of the ECM molecule CSPG by chondroitinase (ChABC) enhnaces neural differentiation in hindbrain primary cultures

Transcriptomics of hindbrain boundaries vs. rhombomeres

Differential expression patterns and functions distinguish hindbrain boundaries (CSPG+) from rhombomeres (CSPG−) cell groups.

(For more details:  Hutchings et al., Development, 2024; dev201934. doi:10.1242/dev.201934)

Abnormal axonal growth in the hindbrain upon FMRP (Fragile-X mental retardation protein) knockout

Axonal paths must be accurate in order to reach target sites and establish circuits. The hindbrain is a hub for key CNS circuits, such as auditory and pre-cerebellar ones. We aim to uncover the assembly of hindbrain neuronal networks, from early stages of neural progenitors, up to generation of axonal circuits. We have developed advanced tools to trace specific types of hindbrain neurons and unraveled promising molecules that regulate their axonal growth. Interesting ones include several Lim-HD transcription factors and the RNA binding protein FMRP . 

(For more details: Wang et al., Development, 2020, dev188797. doi: 10.1242/dev.188797; Kohl et al., The Journal of Neuroscience, 2015, doi: 10.1523/JNEUROSCI.2699-14.2015)

• NEURAL DEVELOPMEANT AS A READOUT FOR ENVIRONMETAL POLLUTION 

The possibility that evironmental pollution impairs embryonic development is an emerging concern, with possible implications on animal and human health. Neural development is highly sensitive to variours external stressors, including chemical pollutants. A main residual pharmaceutical pollutant that persists in the environment is the anti-epileptic drug carbamazepine, an acknowledged teratogen. Although the environmental levels of carbamazepine are much lower than its therapeutic doses, we investigated whether exposing embryos to environmental-relevant levels of carbamazepine affects their developmemt. Strickingly, neural development was severly imapired in chick embryos exposed to environmental-relevant levels of carbamazepinetop in a dose and stage-specific manner. We are expanding this field of research to other species and chemicals, where neural development will serve as a landmark to assess environmental toxicity.