AUTHOR=Tran Hong-Nhung , Nguyen Quy-Hoai , Jeong Yongsu 

TITLE=Dbx1 is a dorsal midbrain-specific determinant of GABAergic neuron fate and regulates differentiation of the dorsal midbrain into the inferior and superior colliculi

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=12

YEAR=2024

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2024.1336308

DOI=10.3389/fcell.2024.1336308

ISSN=2296-634X

ABSTRACT=<p>The mechanism underlying the differentiation of the dorsal midbrain into two morphologically and functionally distinct compartments, the inferior colliculus (IC) and superior colliculus (SC), which process auditory and visual information, respectively, remains largely unexplored. By using null and conditional alleles, we uncover the roles of a homeodomain transcription factor <italic>Dbx1</italic> in the regulation of IC and SC differentiation. We show that <italic>Dbx1</italic> regulates GABAergic neuron development in the dorsal midbrain. In the absence of <italic>Dbx1</italic> function, the dorsal-most m1-m2 progenitor domains in the midbrain fail to activate GABAergic neuron-specific gene expression and instead switch to a glutamatergic phenotype. These results identify <italic>Dbx1</italic> as a dorsal midbrain-specific GABAergic determinant that regulates the selector genes, <italic>Helt</italic>, <italic>Gata2</italic>, and <italic>Tal2</italic>. Furthermore, we demonstrate that maturation of the dorsal midbrain into the IC and SC is dependent on <italic>Dbx1</italic>. Null mutation of <italic>Dbx1</italic> impairs the identity and fate of IC and SC neurons. Surprisingly, <italic>Dbx1</italic> is required for preventing IC into SC fate switch and thus <italic>Dbx1</italic>-deficient IC neurons undergo acquisition of SC identity. Conditional inactivation of <italic>Dbx1</italic> at late developmental phase leads to alteration in the identity and fate of the IC, but not the SC. These results suggest that SC differentiation is dependent on the early function of <italic>Dbx1</italic>, and that the IC requires the prolonged action for its normal formation. Furthermore, we uncover that <italic>Tcf7l2</italic> acts downstream of <italic>Dbx1</italic> selectively to promote IC differentiation. Altogether, our study identifies a molecular mechanism underlying spatial and temporal control of dorsal midbrain development.</p>