Axonal Guidance Molecules in Reproduction

Gonadotropin releasing hormone (GnRH) neurons serve as the pilot light for reproduction in all mammals. GnRH neurons originate from the nasal placode and migrate into the hypothalamus during embryonic development. Disruption of the origin or their migratory journey results in Kallmann Syndrome, a rare Mendelian disorder characterized by hypogonadotropic hypogonadism secondary to GnRH deficiency and anosmia (loss of sense of smell). Recent studies have started to shed new light on the cellular contribution of the GnRH neurons showing that the olfactory placode, a neuroectodermal derivative, as well as neural crest cells serve as precursors to the GnRH neurons. In addition, a complex interplay of axonal guidance cues is also necessary for the migration of GnRH neurons into the brain. Dr. Balasubramanian, in collaboration with Dr. Engle from the Boston Children’s Hospital, recently examined patients harboring a novel missense mutation (p.E410K) in an axonal guidance gene, TUBB3, and demonstrated that this mutation results in a complex syndromic phenotype involving Kallmann Syndrome, referred to as the TUBB3 E410K syndrome. In addition, Dr. Balasubramanian has also defined the mutational allelic spectrum of the CHD7 gene in patients with GnRH deficiency. His ongoing studies, supported by a NICHD K23 Career Development Award, focus on expanding the role of both axonal guidance genes (TUBB3, SEMA3A) as well neural crest genes (SOX10, CHD7) in the pathogenesis of Kallmann Syndrome in humans. 


Principal Investigator: Ravikumar Balasubramanian MD, PhD
Faculty Mentor: William F. Crowley, Jr. MD
Biomedical Research Career Award Fellow: David Keefe, Anna Kutateladze