Transcriptional regulation is essential for the correct functioning of cells during development and in postnatal life. The basic Helix-loop-Helix (bHLH) superfamily of transcription factors is well conserved throughout evolution and plays critical roles in tissue development and tissue maintenance. A subgroup of this family, called neural lineage bHLH factors, is critical in the development and function of the central nervous system. In this review, we will focus on the function of one subgroup of neural lineage bHLH factors, the Neurod family. The Neurod family has four members: Neurod1, Neurod2, Neurod4, and Neurod6. Available evidence shows that these four factors are key during the development of the cerebral cortex but also in other regions of the central nervous system, such as the cerebellum, the brainstem, and the spinal cord. We will also discuss recent reports that link the dysfunction of these transcription factors to neurological disorders in humans.

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The aim of the study is to identify new gene mutations causing cerebral cortex malformations in mice. Materials and Methods. To identify genes causing cerebral cortex malformations, chemical mutagenesis was carried out using N-ethyl-N-nitrosourea as a mutagen. A total of 141 male C3H mice aged 8 weeks were injected with the mutagen in order to induce mutations in spermatogonial stem cells. After a period of sterility, the animals were used in three-generation backcross scheme. Satb2-LacZ reporter mice were involved in this strategy to label the neurons forming the corpus callosum. Results. The animal phenotype displaying primary microcephaly and 6 mutant lines demonstrating audiogenic epilepsy have been described. The phenotypes of these mutants will be further presented and discussed.

The aim of the study was the behavioral phenotyping of mice homo-and heterozygous for the Sip1 gene, which plays an important role in the development of the mammalian cerebral cortex.Materials and Methods. The study was performed on mice hetero-and homozygous for the Sip1 gene; these animal models were developed using the Cre recombination method. At an age of 20-30 days, all animals were exposed to a high-intensity sound to identify predisposition to audiogenic epilepsy. At an age of two months, the males were tested for their general physical health and behavioral phenotypes. The tests included a neurological and sensorimotor assessment, an evaluation of anxiety using the light-dark test, a study on locomotion and general exploration in the open field test, the acoustic startle response and prepulse inhibition, social activity in the Crawley's test and the learning ability as scored by the conditioned reflex of passive avoidance.Results. Mice homozygous for the Sip1 gene never reached the age of two months. In heterozygous mice, a higher occurrence of hind limb extension reflex abnormalities, an increased level of anxiety in the light-dark test, and a decrease in social activity in the Crawley's test were found.Conclusion. The presence of a mutant allele of the Sip1 gene leads to neurologic disorders, an increase in anxiety and a decrease in the social activity of the animals.

Abnormal development of corpus callosum is relatively common and causes a broad spectrum of cognitive impairments in humans. We use acallosal Neurod2/6-deficient mice to study callosal axon guidance within the ipsilateral cerebral cortex. Initial callosal tracts form but fail to traverse the ipsilateral cingulum and are not attracted towards the midline in the absence of Neurod2/6. We show that the restoration of Ephrin-A4 (EfnA4) expression in the embryonic neocortex of Neurod2/6-deficient embryos is sufficient to partially rescue targeted callosal axon growth towards the midline. EfnA4 cannot directly mediate reverse signaling within outgrowing axons, but it forms co-receptor complexes with TrkB (Ntrk2). The ability of EfnA4 to rescue the guided growth of a subset of callosal axons in Neurod2/6-deficient mice is abolished by the co-expression of dominant negative TrkBK571N (kinase-dead) or TrkBY515F (SHC-binding deficient) variants, but not by TrkBY816F (PLCγ1-binding deficient). Additionally, EphA4 is repulsive to EfnA4-positive medially projecting axons in organotypic brain slice culture. Collectively, we suggest that EfnA4-mediated reverse signaling acts via TrkB-SHC and is required for ipsilateral callosal axon growth accuracy towards the midline downstream of Neurod family factors.