Investigating the role of Metabolism Related Genes MRGs CNKSR2 and PHACTR1 in chick forebrain development

Abstract

The vertebrate forebrain develops through a precisely controlled process, which begins with the invagination of the dorsal, morphologically distinct region of the roof plate. In the chick forebrain, it has been observed that the invaginating roof plate acts as a secondary signaling centre that regulates the patterning and morphogenesis of the forebrain. However, the molecular mechanism(s) through which the roof plate regulates forebrain morphogenesis remains unclear to date. It has been observed that the ablation of the roof plate either by physical or genetic means leads to the manifestation of a severe congenital brain disorder called holoprosencephaly (HPE). Holoprosencephaly is quite common with an incidence of 1:250 in conceptuses and 1:10,000 in live births. The underlying reason for this severe brain disorder is the failure of the separation of the cerebral hemispheres during development. HPE has been classified into different sub-types depending on the severity of the disorder, the most severe being alobar holoprosencephaly, where craniofacial and MRI observations show the absence of the cerebral hemispheres and the inability of the eye fields to separate. The other subtypes that are milder include semi-lobar and lobar forms, while the mildest subtype of HPE is known as the middle interhemispheric variant (MIHV). Several factors are associated with HPE, the most common being an improper function of certain genes such as Shh, Zic2, and Six3. Despite the vast number of studies reported in the literature, the precise aetiology of holoprosencephaly is yet to be determined. The invaginating forebrain roof plate in the chick functions as a signaling center wherein BMP signaling, WNT signaling, and Retinoic Acid (RA) signaling is the major pathways. The inhibition of some of these signaling pathways either in the chick forebrain roof plate or the mouse embryo has been shown to cause a holoprosencephaly-like phenotype. However, the following two questions remain to be answered: 1) What are the mole