AMOTL2ND

The Role of AMOTL2 Protein in the Development of the Cerebral Cortex

(Acronym: AMOTL2ND)

Project funded by the National Science Centre under the “PRELUDIUM 23” competition.

Project number: 2024/53/N/NZ3/03243
Project value: 210,000.00 PLN
Funding amount: 210,000.00 PLN
Project duration: from 2025-01-09 to 2028-01-08
Project leader: MSc Ila Joshi

Project Summary:

 The neocortex is a vital brain structure supporting high-order cognitive abilities such as attention, reasoning, emotion, thought, memory, language, and consciousness. To ensure proper functionality, brain structures must communicate through highly specialized cells, the neurons. In the neocortex, six layers of neurons are present: the deep-layer neurons (layers V and VI), which project subcortical regions of the brain, and the upper-layer neurons (layers II/III and IV) making cortico-cortical connections, allowing communication between the two cerebral hemispheres. The cortical neurons’ identity, number, and positioning must be tightly controlled. Indeed, neurodevelopmental disorders such as autism spectrum disorder and epilepsy are associated with defects in the neocortex formation.

All the neurons forming the neocortex are produced from a unique original population of progenitors named radial glial cells (RGCs) during a developmental process called corticogenesis. RGCs are highly polarized and send extensions through the apicobasal axis of the neocortex. Their apical feet, attached to the ventricular surface, receive signals from the cerebrospinal fluid, while their basal feet are accountable for the neuronal migration process. This apicobasal cytoarchitecture is established and maintained by adherens junction and polarity proteins precisely arranged at the ventricular (apical) and pia (basal) membranes. RGC extensions are essential as they allow the reception of signals transmitted by the surrounding environment (i.e., cerebrospinal fluid, neurons produced, and neighboring progenitors), which regulate the proliferation/differentiation balance. Lastly, the choice of progenitor between proliferating to expand the progenitor pool or to differentiate into a neuron is critical. Overproliferation results in the excessive production of neurons, leading to a neurological disorder called megalencephaly. Conversely, a precocious differentiation into neurons, depleting the pool of progenitors, will reduce the total number of neurons produced, leading to microcephaly.

Among the molecules involved in the proliferation/differentiation balance regulation, the Hippo/YAP and the Wnt/β-catenin pathways play a significant role. Interestingly, Angiomotin-like 2 (AMOTL2) is known to be a key regulator of these two pathways in other physiological and pathological models but has never been studied in the context of brain development. AMOTL2 is a member of the Angiomotins family that also works as a scaffold for properly arranging and organizing the adherens junction and polarity proteins. Therefore, it has been studied to regulate various processes such as embryo development, blastocyte hatching, and angiogenesis. Considering the importance of AMOTL2 in regulating cellular organization and proliferation in other systems and knowing the critical role of these processes in regulating RGCs, I hypothesized that AMOTL2 might be an essential anchor in modulating RGCs during corticogenesis.

My project aims to characterize the expression and function of AMOTL2 during corticogenesis. I plan to analyze the expression pattern of AMOTL2 at different time points of corticogenesis and examine the impact of AMOTL2 deletion on the progenitor and neuronal populations in the developing and mature neocortex. I will also analyze the potential influence of AMOTL2 in the adhesion, polarity, and proliferation/differentiation balance in RGCs during corticogenesis. Lastly, I aim to address the possible perturbation of the Hippo/YAP and Wnt/β-catenin pathways upon AMOTL2 deletion, leading to impaired cortical thickness.

Altogether, my project will show the involvement of AMOTL2 in the regulation of corticogenesis for the first time. Moreover, this project will provide a better insight into the complex mechanisms controlling brain development and their participation in the etiology of various neurological and neurodevelopmental disorders.