Molecular Mechanisms Governing Development of the Hypothalamus

hypothalamus;development;patterning;Wnt;Foxd1;Neuroscience

Newman, ElizabethSockanathan, Shanthini ;

Johns Hopkins University

关键词: hypothalamus;    development;    patterning;    Wnt;    Foxd1;    Neuroscience;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/60220/NEWMAN-DISSERTATION-2017.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

The hypothalamus is a small, but anatomically and functionally complex, region of the brain.Due in part to its anatomical complexity, its development is not well understood.Here, we have explored its development by studying two different patterning mechanisms:intrinsic factors, in the form of the transcription factor Foxd1, and extrinsic factors, via the canonical Wnt signaling pathway.Foxd1 is expressed broadly throughout the hypothalamus and prethalamus early in development, but its function was unknown.We generated Foxd1-/- mice and used a panel of in situ hybridization markers to study their development.These mice have a very selective defect in the anterior hypothalamus, specifically the suprachiasmatic nucleus, periventricular nucleus and paraventricular nucleus. RNA-Seq analysis suggests that Foxd1 may be controlling anterior hypothalamic development through regulation of the transcription factors Six3 and Vax1.We also studied the role of canonical Wnt signaling in the patterning of the hypothalamus and prethalamus by manipulating its effector protein, β-catenin by using Foxd1-Cre, which is expressed in both the hypothalamus and prethalamus.Loss of β-catenin resulted in an anteriorization of the hypothalamus.Posterior structures were lost or reduced, and anterior structures were expanded.We also generated a mouse with constitutively active β-catenin through excision of its autoinhibitory domain.In situ hybridization analysis of these mice revealed a complex phenotype where there was a general loss of most, but not all, markers of regional and nuclear identity.However, the posterior hypothalamus was not only preserved, but potentially expanded.In neither the loss- or gain-of-function mice was the patterning of the prethalamus affected.However, in the gain-of-function mice, the prethalamus was only partially differentiated.We next manipulated the Shh signaling pathway by generating a constitutively active form of its effector protein, Smo, which had no effect on patterning in the hypothalamus or prethalamus.However, by crossing the constitutively active Smo mice to our constitutively active β-catenin mice, we were able to rescue the defects observed in the constitutively active β-catenin single mutant mice.Thus, we have revealed an important interaction between two major signaling pathways in the development of the hypothalamus.We have identified multiple novel mechanisms controlling development of the hypothalamus, although further research will need to be done to determine the exact methods by which they are directing patterning and differentiation.